Variable diameter cannula and methods for controlling insertion depth for medicament delivery

ABSTRACT

An apparatus includes a microneedle that defines a lumen therethrough. The microneedle has a proximal end portion a distal end portion and a hub portion between the proximal end portion and the distal end portion. The proximal end portion is configured to be coupled to a medicament container, such as, for example a syringe. The portion of the lumen within the proximal end portion has a first diameter. The distal end portion is configured to pierce a target tissue. The portion of the lumen within the distal end portion has a second diameter smaller than the first diameter. The hub portion includes a surface configured to contact the target tissue when the distal end portion is disposed with the target tissue.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of International Application No.PCT/US2015/036715, entitled “Variable Diameter Cannula and Methods forControlling Insertion Depth for Medicament Delivery,” filed Jun. 19,2015, which claims priority to and the benefit of U.S. ProvisionalPatent Application Ser. No. 62/035,682, entitled “Apparatus and Methodsfor Controlling the Insertion Depth of a Needle,” filed Aug. 11, 2014and U.S. Provisional Patent Application Ser. No. 62/014,766, entitled“Variable Diameter Cannula for Medicament Delivery,” filed Jun. 20,2014, each of which is incorporated herein by reference in its entirety.

BACKGROUND

The embodiments described herein relate generally to the field ofophthalmic therapies and more particularly to the use of a microneedlefor delivery and/or removal of a substance, such as a fluid therapeuticagent into and/or from ocular tissues for treatment of the eye.

Although needles are used in transdermal and intraocular drug delivery,there remains a need for improved microneedle devices and methods,particularly for delivery of substances (e.g., drugs) into the posteriorregion of the eye. Many inflammatory and proliferative diseases in theposterior region (or other regions) of the eye require long-termpharmacological treatment. Examples of such diseases include maculardegeneration, diabetic retinopathy, and uveitis. It is often difficultto deliver effective doses of a drug to the back of the eye usingconventional delivery methods such as topical application or anintravitreal administration (IVT), which has poor efficacy, and systemicadministration, which often causes significant side effects. Forexample, while eye drops are useful in treating conditions affecting theexterior surface of the eye or tissues at the front of the eye, the eyedrops are often not sufficiently conveyed to the back of the eye, as maybe required for the treatment of some of the retinal diseases listedabove.

Although there have been advances in the past decade regarding theutilization of systemically delivered substances, there are obstacles towide spread adoption of such methods. For example, in certainsituations, direct injection into the eye (e.g., into the vitreous)using conventional 27 gauge or 30 gauge needles and syringes can beeffective. Direct injection, however, can be associated with significantsafety risks, and physicians often require professional training toeffectively perform such methods. Moreover, in some instances, targetedinjection of a therapeutic agent is desirable. In such instances,however, the relatively small anatomic structures of the eye oftenresult in significant challenges to placing a needle at a targetlocation using known devices and methods, especially as they pertain toplacing the distal end of the needle at the desired depth within theeye. Furthermore, IVT administration can have side effects such asincreased intraocular pressure or faster onset of cataract formation.

In addition, many known methods of direct injection of a drug into theeye include inserting a needle or a cannula at an acute angle relativeto a surface of the eye, which can make controlling the depth ofinsertion challenging. For example, some such methods includecontrolling the angular orientation of the needle such that the injectedsubstance exits the needle at a particular location. Moreover, someknown methods of injecting substances into ocular tissue include usingcomplicated visualization system or sensors to control the placement ofthe needle or cannula.

Known devices for ocular injection do not provide the mechanism foradjusting needle length so that the needle can be inserted into the eyeto the desired depth. Known systems also do not provide a reliablemechanism for determining when the needle tip is in the desiredlocation, for example, the suprachoroidal space (SCS) of the eye. Suchshortcomings in known systems and methods are exacerbated because thesize and thickness of various layers included in the eye can varysubstantially from one person to another. For example, the thickness ofthe conjunctiva and the sclera can be substantially different and theirtrue value cannot easily be predetermined via standard techniques.Furthermore, the thickness of these layers can also be different indifferent portions of the eye and at different times of the day in thesame eye and location. Therefore, using known systems and methods it canbe challenging to determine and/or adjust the length of the needle forpuncturing the eye, such that a tip of the needle is at the desireddepth, for example, the SCS. Too short a needle might not penetrate thesclera, and too long a needle can traverse beyond the SCS and damage theretina of the eye. Further, known systems do not provide a convenientway to detect the position of the needle tip within the eye.

Because of the sensitivities associated with intraocular injection(e.g., the sensitivity of the tissue, the potential impact onintraocular pressure and the like), many known systems involve manualinjection, often using needles and/or cannulas having a small diameter(e.g., 27 gauge, 30 gauge, or even smaller) and lengths of 12 mm, 15 mmor even longer. More particularly, many known devices and methodsinclude the user manually applying a force (e.g., via pushing a plungerwith their thumb or fingers) to expel a fluid (e.g., a drug) into theeye. Because of the small needle size and/or the characteristics of theinjected drug, some such devices and methods involve the use of forcelevels higher than that which users are comfortable with applying. Forexample, some studies have shown that users generally do not like toapply more than 2 N force against the eye during ocular injection.Accordingly, in certain situations a user may not properly deliver themedicament using known systems and methods because of their reluctanceto apply the force to fully expel the medicament.

Moreover, injection into different target layers of the eye can causevariability in the amount of the force required for insertion of theneedle and/or injection of the medicament. Different layers of the eyecan have different densities. For example, the sclera generally has ahigher density than the conjunctiva or the SCS. Differences in thedensity of the target region or layer can produce different backpressureagainst the needle exit, i.e., the tip of the needle from which thefluid emerges. Thus, injection into a relatively dense ocular materialsuch as sclera requires more motive pressure to expel the medicamentfrom the needle than is required when injecting a medicament into theSCS.

Furthermore, the injection force to expel the medicament also depends onthe density and viscosity of the liquid medicament, length of theneedle, and/or diameter of the needle. To inject certain medicamentsinto the eye via desired needles (e.g., 27 gauge, 30 gauge, or evensmaller) can require more force than many practitioners are comfortable(or capable of) applying.

Thus, a need exists for improved devices and methods, which can assistin facilitating injection of a viscous medicament into ocular tissue.

SUMMARY

In some embodiments, an apparatus includes a microneedle that defines alumen therethrough. The microneedle has a proximal end portion a distalend portion and a hub portion between the proximal end portion and thedistal end portion. The proximal end portion is configured to be coupledto a medicament container, such as, for example a syringe. The portionof the lumen within the proximal end portion has a first diameter. Thedistal end portion is configured to pierce a target tissue. The portionof the lumen within the distal end portion has a second diameter smallerthan the first diameter. The hub portion includes a surface configuredto contact the target tissue when the distal end portion is disposedwith the target tissue.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a cross-sectional view of an illustration of the human eye.

FIG. 2 is a cross-sectional view of a portion of the human eye of FIG. 1taken along the line 2-2.

FIGS. 3 and 4 are cross-sectional views of a portion of the human eye ofFIG. 1 taken along the line 3-3, illustrating the suprachoroidal spacewithout and with, respectively, the presence of a fluid.

FIG. 5 is a schematic illustration of an apparatus that includes anactuation rod and a microneedle, according to an embodiment.

FIG. 6 is a cross-sectional view of a microneedle, according to anembodiment.

FIG. 7 is a perspective view of a medical injector, according to anembodiment.

FIG. 8 is an exploded view of the medical injector of FIG. 7.

FIG. 9 is an exploded view of the needle assembly of FIG. 7.

FIG. 10 is a cross-sectional view of the needle assembly of FIG. 9,taken along line 10-10.

FIG. 11A is an exploded view of a needle assembly, according to anembodiment.

FIG. 11B is a side view of the needle assembly of FIG. 11A, in anassembled configuration.

FIG. 11C is a cross-sectional view of the needle assembly of FIG. 11A,in an assembled configuration.

FIG. 12 is a schematic illustration of an apparatus that includes amedical injector, a compressible member and a hub, according to anembodiment.

FIG. 13 is a side cross-sectional view of the apparatus of FIG. 12 in afirst configuration.

FIG. 14 is a side cross-sectional view of the apparatus of FIG. 12 in asecond configuration.

FIG. 15 is a side cross-sectional view of the apparatus of FIG. 12 in athird configuration.

FIG. 16 is a side cross-sectional view of a portion of an apparatus thatincludes a medical injector, a compressible member, a hub, and astopping mechanism in a first configuration, according to an embodiment.

FIG. 17 is a side cross-sectional view of the apparatus of FIG. 16 in asecond configuration.

DETAILED DESCRIPTION

The embodiments described herein relate to systems and devices fordelivering a fluid (e.g., a drug) into or extracting a fluid from thesclera of an eye. Furthermore, embodiments described herein are relatedto microneedles and/or delivery cannulas configured to convey a viscousmedicament into ocular tissue. Embodiments described herein are alsorelated to systems, devices, and methods for controlling the insertiondepth of a delivery member, such as, for example, a microneedle, intothe eye to deliver a therapeutic agent to, for example, a posteriorregion of the eye (e.g., via the suprachoroidal space). Embodiments,described herein are also related to microneedles and/or deliverycannulas configured to form a substantially fluid-tight seal around adelivery passageway formed by insertion of a delivery member, forexample, a microneedle, into the eye to prevent leakage of the substanceand/or ocular fluid from the insertion site.

In some embodiments, the microneedles included in the embodimentsdescribed herein include a bevel at the distal tip, which allows forease of penetration into the sclera and/or suprachoroidal space withminimal collateral damage. Moreover, in some embodiments, themicroneedles disclosed herein can define a narrow lumen (e.g., gaugesize greater than or equal to 30 gauge, 32 gauge, 34 gauge, 36 gauge,etc.) to allow for suprachoroidal drug delivery while minimizing thediameter of the needle track caused by the insertion of the microneedle.In some embodiments, the lumen and bevel aspect ratio of themicroneedles described herein are distinct from standard 27 gauge and 30gauge needles, which are now commonly used for intraocular injection.For example, the microneedles included in the embodiments describedherein can be any of those described in International Patent ApplicationPublication No. WO2014/036009, entitled, “Apparatus and Methods for DrugDelivery Using Microneedles,” filed on Aug. 27, 2013, the disclosure ofwhich is incorporated by reference herein in its entirety (referred tohenceforth as the “'009 PCT application”).

In some embodiments, an apparatus includes a microneedle that defines alumen therethrough. The microneedle has a proximal end portion a distalend portion and a hub portion between the proximal end portion and thedistal end portion. The proximal end portion is configured to be coupledto a medicament container, such as, for example a syringe. The portionof the lumen within the proximal end portion has a first diameter. Thedistal end portion is configured to pierce a target tissue. The portionof the lumen within the distal end portion has a second diameter smallerthan the first diameter. The hub portion includes a surface configuredto contact the target tissue when the distal end portion is disposedwith the target tissue.

In some embodiments, an apparatus includes a microneedle that defines alumen therethrough. The microneedle has a proximal end portion a distalend portion and a hub portion between the proximal end portion and thedistal end portion. The portion of the lumen within the hub portion ischaracterized by a diameter that changes along a longitudinal axis ofthe lumen. Similarly stated, the diameter of the lumen varies within thehub portion from a first diameter at the proximal end portion to asecond, smaller diameter at the distal end portion. The hub portion ofthe microneedle has a convex distal end surface, which is configured tocontact a target surface of a target tissue when a substance is conveyedthrough the needle into the target tissue. In some embodiments, thedistal end surface includes a sealing portion configured to define asubstantially fluid-tight seal with the target surface when the distalend surface is in contact with the target surface.

In some embodiments, a method includes inserting a distal end portion ofa needle of a medical injector into a target tissue to define a deliverypassageway within the target tissue. This is followed by placing aconvex hub surface of the needle into contact with a target surface ofthe target tissue to fluidically isolate the delivery passageway. Next,the method includes conveying, after the placing, a substance into thetarget tissue via the needle. The conveying includes conveying thesubstance through a proximal end portion of the needle having a firstdiameter and the distal end portion of the needle having a seconddiameter. In some embodiments, the target tissue is an eye and thetarget surface is the conjunctiva of the eye. In some embodiments, thedelivery passageway extends through a sclera of the eye and theconveying includes conveying the substance into at least one of asuprachoroidal space or lower portion of the sclera. In suchembodiments, the method can further include adjusting, before theconveying, a length of the needle extending from the distal end surfaceof the hub.

In some embodiments, a method includes inserting a distal end portion ofa needle of a medical injector into a target tissue to define a deliverypassageway within the target tissue. The inserting is performed suchthat a centerline of the needle is substantially normal to a targetsurface of the target tissue. This is followed by placing a distal endsurface of a hub of the needle into contact with a target surface of thetarget tissue to fluidically isolate the delivery passageway. Next, themethod includes conveying, after the placing, a substance into thetarget tissue via the needle. In some embodiments, the delivery isperformed such that a centerline of the delivery passageway and asurface line tangent to the target surface defines an angle of entry ofbetween about 75 degrees and about 105 degrees.

In some embodiments, an apparatus includes a hub and a puncture member.The hub is configured to be coupled to a medicament container. A distalend surface of the hub is configured to contact a target surface of atarget tissue. The puncture member is coupled within the passageway ofthe hub. When the hub is coupled to the medicament container, thepuncture member defines a lumen therethrough in fluid communication withthe medicament container. A distal end portion of the puncture memberextends distally from the distal end surface of the hub. A proximal endportion of the puncture member defines a first inner diameter and thedistal end portion of the puncture member defines a second innerdiameter. The second inner diameter is smaller than the first innerdiameter.

In some embodiments, an apparatus includes a medicament container, ahub, and a microneedle. The medicament container contains a medicamenthaving a viscosity of at least about 100 centiPoise. An actuation rod isdisposed in the medicament container. The hub is configured to becoupled to the medicament container. The hub defines a passageway. Adistal end surface of the hub is configured to contact a target surfaceof a target tissue. The microneedle is coupled within the passageway ofthe hub. When the hub is coupled to the medicament container, themicroneedle defines a lumen in fluid communication with the medicamentcontainer. A distal end portion of the microneedle extends distally fromthe distal end surface of the hub. The distal end portion of themicroneedle defines an inner diameter being 30 gauge or smaller. Alength of the distal end portion of the microneedle being such that themedicament is conveyed through the lumen when a force of less than about6 N is exerted on the actuation rod. In some embodiments, the length issuch that the medicament is conveyed through the lumen at a flow rate ofbetween about 0.1 μL/sec and about 10 μL/sec when a force of less thanabout 6 N is exerted on the actuation rod. In some embodiments, thelength is such that the medicament is conveyed through the lumen at aflow rate of at least about 1.0 μL/sec.

In some embodiments, an apparatus includes a medicament container, ahub, and a needle. The medicament container contains a medicament, andincludes an elastomeric member disposed therein such that movement ofthe elastomeric member conveys the medicament within the medicamentcontainer. The hub is configured to be coupled to the medicamentcontainer. The needle is configured to be coupled to the medicamentcontainer via the hub. The needle defines a lumen in fluid communicationwith the medicament container. A distal end portion of the needledefines an inner diameter being 30 gauge or smaller, and has a length ofbetween about 200 microns and about 1500 microns. A proximal end portionof the needle defines an inner diameter being 27 gauge or bigger. Theneedle includes a transition portion between the proximal end portionand the distal end portion. An outer surface of the transition portionconfigured to contact a target surface of a target tissue during aninjection event.

In some embodiments, an apparatus includes a medicament containerassembly, a needle, a hub, and a compressible member. The needle is influid communication with the medicament container assembly. The hub isconfigured to be operatively coupled to a distal end portion of themedicament container assembly. The hub defines a first passageway. Adistal end surface of the hub is configured to contact a target surfaceof a target tissue. The compressible member is disposed between the huband the distal end portion of the medicament container assembly. Thecompressible member defines a second passageway, and the firstpassageway and the second passageway are aligned to receive at least aportion of the needle therethrough. The compressible member isconfigured to be compressed in response to a force exerted on themedicament container assembly such that a thickness of the compressiblemember reduces from a first thickness to a second thickness.

As used herein, the singular forms “a,” “an”, and “the” include pluralreferents unless the context clearly dictates otherwise. Thus, forexample, the term “a member” is intended to mean a single member or acombination of members, “a material” is intended to mean one or morematerials, or a combination thereof.

As used herein, the words “proximal” and “distal” refer to the directioncloser to and away from, respectively, an operator (e.g., surgeon,physician, nurse, technician, etc.) who would insert the medical deviceinto the patient, with the tip-end (i.e., distal end) of the deviceinserted inside a patient's body first. Thus, for example, the end of amicroneedle described herein first inserted inside the patient's bodywould be the distal end, while the opposite end of the microneedle(e.g., the end of the medical device being manipulated by the operator)would be the proximal end of the microneedle.

As used herein, a “set” can refer to multiple features or a singularfeature with multiple parts. For example, when referring to set ofwalls, the set of walls can be considered as one wall with distinctportions, or the set of walls can be considered as multiple walls.

As used herein, the terms “about” and “approximately” generally meanplus or minus 10% of the value stated. For example, about 0.5 wouldinclude 0.45 and 0.55, about 10 would include 9 to 11, about 1000 wouldinclude 900 to 1100.

As used herein, the terms “delivery member”, “puncture member”, and“puncturing member” are used interchangeably to refer to an articleconfigured to pierce tissue layers and deliver a substance to a targettissue layer, for example, a needle or a microneedle.

As used herein, the terms “medicament container”, and “medicamentcontainment chamber” are used interchangeably to refer to an articleconfigured to contain a volume of a substance, for example, amedicament.

The term “fluid-tight” is understood to encompass both a hermetic seal(i.e., a seal that is gas-impervious) as well as a seal that isliquid-impervious. The term “substantially” when used in connection with“fluid-tight,” “gas-impervious,” and/or “liquid-impervious” is intendedto convey that, while total fluid imperviousness is desirable, someminimal leakage due to manufacturing tolerances, or other practicalconsiderations (such as, for example, the pressure applied to the sealand/or within the fluid), can occur even in a “substantiallyfluid-tight” seal. Thus, a “substantially fluid-tight” seal includes aseal that prevents the passage of a fluid (including gases, liquidsand/or slurries) therethrough when the seal is maintained at a constantposition and at fluid pressures of less than about 5 psig, less thanabout 10 psig, less than about 20 psig, less than about 30 psig, lessthan about 50 psig, less than about 75 psig, less than about 100 psigand all values in between. Similarly, a “substantially liquid-tight”seal includes a seal that prevents the passage of a liquid (e.g., aliquid medicament) therethrough when the seal is maintained at aconstant position and is exposed to liquid pressures of less than about5 psig, less than about 10 psig, less than about 20psig, less than about30 psig, less than about 50 psig, less than about 75 psig, less thanabout 100 psig and all values in between.

The embodiments and methods described herein can be used to treat,deliver substances to and/or aspirate substances from, various targettissues in the eye. For reference, FIGS. 1-4 are a various views of ahuman eye 10 (with FIGS. 2-4 being cross-sectional views). Whilespecific regions are identified, those skilled in the art will recognizethat the proceeding identified regions do not constitute the entirety ofthe eye 10, rather the identified regions are presented as a simplifiedexample suitable for the discussion of the embodiments herein. The eye10 includes both an anterior segment 12 (the portion of the eye in frontof and including the lens) and a posterior segment 14 (the portion ofthe eye behind the lens). The anterior segment 12 is bounded by thecornea 16 and the lens 18, while the posterior segment 14 is bounded bythe sclera 20 and the lens 18. The anterior segment 12 is furthersubdivided into the anterior chamber 22, between the iris 24 and thecornea 16, and the posterior chamber 26, between the lens 18 and theiris 24. The cornea 16 and the sclera 20 collectively form a limbus 38at the point at which they meet. The exposed portion of the sclera 20 onthe anterior segment 12 of the eye is protected by a clear membranereferred to as the conjunctiva 45 (see e.g., FIGS. 2 and 3). Underlyingthe sclera 20 is the choroid 28 and the retina 27, collectively referredto as retinachoroidal tissue. A vitreous humour 30 (also referred to asthe “vitreous”) is disposed between a ciliary body 32 (including aciliary muscle and a ciliary process) and the retina 27. The anteriorportion of the retina 27 forms an ora serrata 34. The loose connectivetissue, or potential space, between the choroid 28 and the sclera 20 isreferred to as the suprachoroid. FIG. 2 illustrates the cornea 16, whichis composed of the epithelium 40, the Bowman's layer 41, the stroma 42,the Descemet's membrane 43, and the endothelium 44. FIG. 3 illustratesthe sclera 20 with surrounding Tenon's Capsule 46 or conjunctiva 45,suprachoroidal space 36, choroid 28, and retina 27, substantiallywithout fluid and/or tissue separation in the suprachoroidal space 36(i.e., the in this configuration, the space is “potential”suprachoroidal space). As shown in FIG. 3, the sclera 20 has a thicknessbetween about 500 μm and 700 μm. FIG. 4 illustrates the sclera 20 withthe surrounding Tenon's Capsule 46 or the conjunctiva 45, suprachoroidalspace 36, choroid 28, and retina 27, with fluid 50 in the suprachoroidalspace 36.

As used herein, the term “suprachoroidal space,” or SCS which issynonymous with suprachoroid, or suprachoroidia, describes the space (orvolume) and/or potential space (or potential volume) in the region ofthe eye 10 disposed between the sclera 20 and choroid 28. This regionprimarily is composed of closely packed layers of long pigmentedprocesses derived from each of the two adjacent tissues; however, aspace can develop in this region because of fluid or other materialbuildup in the suprachoroidal space and the adjacent tissues. Thesuprachoroidal space can be expanded by fluid buildup because of somedisease state in the eye or because of some trauma or surgicalintervention. In some embodiments, the fluid buildup is intentionallycreated by the delivery, injection and/or infusion of a drug formulationinto the suprachoroid to create and/or expand further the suprachoroidalspace 36 (i.e., by disposing a drug formulation therein). This volumemay serve as a pathway for uveoscleral outflow (i.e., a natural processof the eye moving fluid from one region of the eye to the other through)and may become a space in instances of choroidal detachment from thesclera.

The dashed line in FIG. 1 represents the equator of the eye 10. In someembodiments, the insertion site of any of the microneedles and/ormethods described herein is between the equator and the limbus 38 (i.e.,in the anterior portion 12 of the eye 10) For example, in someembodiments, the insertion site is between about two millimeters and 10millimeters (mm) posterior to the limbus 38. In other embodiments, theinsertion site of the microneedle is at about the equator of the eye 10.In still other embodiments, the insertion site is posterior the equatorof the eye 10. In this manner, a drug formulation can be introduced(e.g., via the microneedle) into the suprachoroidal space 36 at the siteof the insertion and can flow through the suprachoroidal space 36 awayfrom the site of insertion during an infusion event (e.g., duringinjection).

In some embodiments, a system for ocular injection can include amedicament container and a cannula (also referred to as a microneedle)that facilitates delivery of a substance disposed in a medicamentcontainer to a target tissue, for example, the SCS. For example, FIG. 5shows a system 100, according to an embodiment. The system 100 includesan actuation rod 120, a plug 128 (or elastomeric member), a medicamentcontainer 130, and a microneedle 140. The system 100 can be configuredto deliver a medicament to region and/or a layer of a target location,for example, an eye of a patient, (e.g., to the SCS of the eye), asdescribed herein.

The actuation rod 120 includes a proximal end portion 122 and a distalend portion 124. The proximal end portion 122 is configured to receive aforce F (e.g., a force manually applied by a user) to facilitateinjection of a medicament M, as described herein. In some embodiments,the system 100 can include an injection assist assembly (not shown inFIG. 5) operatively connected to actuation rod 120 that is configured toassist in the production of the force F. In such embodiments, theinjection assist assembly can produce at least a portion of the force Fto move the actuation rod 120 within the medicament container 130. Insome embodiments, the injection assist assembly can include an energystorage member, such as a helical spring, compression, extension, springwashers, Belleville washer, tapered, any other type of spring. In otherembodiments, an injection assist assembly could include a compressed gascontainer, or a container containing a propellant. The injection assistassembly can be any of those described in U.S. patent application Ser.No. 14/268,687, entitled, “Apparatus and Methods for Ocular Injection,”filed on May 2, 2014, the disclosure of which is incorporated byreference herein in its entirety.

A distal end portion 124 of the actuation rod 120 is disposed within themedicament container 130. The distal end portion 124 can be coupled toand/or in contact with a plug 128 (also referred to as a plunger,stopper or elastomeric member), which is in fluidic communication with asubstance M (e.g., a medicament such as, for example, VEGF, a VEGFinhibitor, a combination thereof, or any other medicament describedherein) disposed within an internal volume defined by the medicamentcontainer 130. The distal end portion 124 of the actuation rod 120 isconfigured to be displaced within the internal volume defined by themedicament container 130, for example, due to the force F produced by anoperator's thumb (or an injection assist mechanism), as describedherein. In this manner, the actuation rod 120 can displace the plug 128within the medicament container 130 to draw in or expel the substance Mfrom the distal end portion 142 of the microneedle 140, as describedherein. The sidewalls of the plug 128 can be configured to contact thesidewalls of the medicament container 130 such that the plug 128 forms asubstantially fluid-tight seal with the side wall of the medicamentcontainer 130, for example, to prevent leakage of the substance M. Theplug 128 can be made of an inert and/or biocompatible material which isrigid but soft. Example materials include rubber, silicone, plastic,polymers, any other suitable material or combination thereof. In someembodiments, the plug 128 can be monolithically formed with theactuation rod 120.

The microneedle 140 includes a proximal end portion 143, a distal endportion 142 and a hub portion 144, and defines a lumen 141 therethrough.The proximal end portion 143 can be coupled to the medicament container130 to place the lumen in fluid communication with the medicamentcontainer 130. The proximal end portion 143 can include any suitablecoupling features, for example, Luer connectors, threads, snap-fit,latch, lock, friction fit, or any other suitable coupling features.

The distal end portion 142 of the microneedle 140 can define a sharp tipand/or bevel such that the needle 140 is configured to pierce a targetlocation T, for example, a bodily tissue (e.g., ocular tissue). In thismanner, the distal end portion 142 can be disposed within a first regionR1 and/or a second region R2 of the target location T, as describedherein. The bevel, which allows for ease of penetration into the scleraand/or suprachoroidal space with minimal collateral damage. In someembodiments, the lumen and bevel aspect ratio of the microneedlesdescribed herein are distinct from standard 27 gauge and 30 gaugeneedles. For example, the microneedles included in the embodimentsdescribed herein can be any of those described in International PatentApplication Publication No. WO2014/036009, entitled, “Apparatus andMethods for Drug Delivery Using Microneedles,” filed on Aug. 27, 2013,the disclosure of which is incorporated by reference herein in itsentirety (referred to henceforth as the “'009 PCT application”).

The hub portion 144 of the microneedle 140 is disposed between theproximal end portion 143 of the needle 140 and distal end portion 142 ofthe needle 140. The hub portion 144 serves as a transition area betweenthe proximal end portion 143 of the needle and the distal end portion142 of the needle. The hub portion 144 can be substantially arched inshape as shown in FIG. 5, and includes a contact surface 145. Thecontact surface 145 of the hub portion 144 is configured to make contactwith the eye. In this manner the contact surface 145 can control thedepth of penetration of the distal end portion 142 and/or can form afluidic seal with the surface of the eye, as described herein.

The microneedle 140 defines a lumen 141, which is in fluidiccommunication with the substance M disposed within the internal volumedefined by the medicament container 130. In this manner, the microneedle140 is configured to establish fluid communication between themedicament container 130 and the target location T, for example, thefirst region R1 and/or the second region R2 of the target location T. Insome embodiments, the target location T can be an eye such that thefirst region R1 is a suprachoroidal space of the eye, and the secondregion R2 is a sclera of the eye. The lumen 141 of the microneedle 140can be of any suitable size or diameter. More particularly, the portionof the lumen within the proximal end portion 143 is characterized by afirst diameter and the portion of the lumen within the distal endportion 142 is characterized by a second diameter that is smaller thanthe first diameter. Similarly stated, the microneedle 140 has aspatially varying inner diameter. In this manner, the length of thesmaller diameter portion (i.e., the distal end portion 142) can beminimized to reduce the frictional losses associated with conveying themedicament through the microneedle 140. Reducing the frictional losseswill, in turn, reduce the force F and/or the internal pressure that isapplied by the actuation rod 120 to convey the medicament M. In certaincircumstances, the pressure of the medicament M within the medicamentcontainer 130 can be modeled by the Hagen-Poiseuille law, as indicatedbelow:

P=(8*μ*L*Q)/(Π*R ⁴)   (1)

where P is the pressure of the medicament M within the medicamentcontainer 130, μ is the viscosity of the medicament M, L is the lengthof the needle 140, Q is the flow rate of the medicament M through theneedle 140, and R is the radius of the lumen defined by the needle 140.Because the pressure (and/or force) required to inject a high viscosityfluid through a small-bore needle is proportional to the inverse of theradius of the lumen of the needle to the fourth power, the pressure ofthe medicament M within the medicament container 130 necessary toachieve the desired flow rate can, at times, be relatively high. Byreducing the length of the small-diameter portion of the microneedle140, the force requirement to produce a desired injection can beminimized. For example, if the second diameter is 30 gauge or smaller, alength of the distal end portion 142 can be such that the medicament isconveyed through the lumen 141 when a force F of less than about 6 N isexerted on the actuation rod 122 (or the elastomeric member). In someembodiments, the length is such that the medicament is conveyed throughthe lumen at a flow rate of between about 0.1 μL/sec and about 10 μL/secwhen a force of less than about 6N is exerted on the actuation rod. Insome embodiments, the length is such that the medicament is conveyedthrough the lumen at a flow rate of at least about 1.0 μ/sec.

In use, an operator (e.g., a doctor, technician, nurse, physician,ophthalmologist, etc.) can manipulate the system 100 to insert themicroneedle 140 into, for example, an ocular tissue. In this manner, thedistal end portion 142 of the microneedle 140 can be advanced within thetarget tissue to pierce the sclera and place the contact surface 145 ofthe hub portion 144 in contact with an outer surface of the sclera(e.g., the sclera 20 of the eye 10 in FIG. 1). The distal tip of themicroneedle 140 can be moved further proximally relative to the oculartissue to place the lumen 141 of the microneedle 140 in fluidcommunication with the suprachoroidal space (e.g., the suprachoroidalspace 36 of the eye 10 in FIG. 1, or region R1 in FIG. 5). With thelumen 141 of the microneedle 140 in fluid communication with thesuprachoroidal space, the actuation rod 120 can be moved relative to themedicament container 130 from its first position to its second position.With the distal end portion 124 of the actuation rod 120 forming asubstantially fluidic seal (i.e., a substantially hermetic seal) with aninner surface of the medicament container 130, the movement of theactuation rod 120 to its second position expels the drug formulation(contained within the inner volume of the medicament container 130)through the lumen 141 of the microneedle 140. Thus, the medical injector100 can deliver the drug formulation M to the SCS of the eye and thedrug formulation can flow within the suprachoroidal space to bedelivered to, for example, the posterior region of the eye.

The medicament container 130 is configured to contain a medicament Mhaving a high viscosity (i.e., a medicament having a viscosity of atleast 100 centiPoise). The medicament M can be any medicament suitablefor being injected into a body, such as any of the medicaments or othertherapeutic formulations (including biologics, cells or the like) asdescribed herein. For example, in some embodiments, the medicament M canbe a high viscosity substance for treatment of the eye (e.g., gel-likesubstance, a paste-like substance, an emulsion including both a liquidcomponent and a solid component, or the like.) In some embodiments, themedicament M can have a viscosity of at least about 1000 centiPoise. Insome embodiments, the medicament M can have a viscosity of at leastabout 10,000 centiPoise. In other embodiments, the medicament M can havea viscosity of at least 100,000 centiPoise (cps). In other embodiments,the medicament M can have a viscosity of between about 40,000 cps andabout 60,000 cps. As described above, the amount of kinetic energyrequired to move the actuation rod 120 within the medicament container130 is dependent on, among other things, the viscosity of the medicamentM, the desired flow rate of the medicament M through the distal endportion 142 of the microneedle 140, the length of the microneedle 140and/or the size of the lumen 141 defined by the needle 140. Oneadvantage of the present invention is its ability to reduce the lengthof the distal portion 142 of the microneedle 140 which in turn, greatlyreduces friction losses. In doing so the operator of system 100 canadminister the medicament M through a limited amount of force F.

FIG. 6 is a cross-sectional view of a microneedle 240 according to anembodiment. The microneedle 240 includes a proximal end portion 243, adistal end portion 242, a hub portion 244 and defines a lumen 241therethrough. Although shown as being a blunt end, the distal endportion 242 of the microneedle 240 can define a sharp tip and/or bevelsuch that the needle 240 can pierce a target location. The hub portion244 of the microneedle 240 is disposed between the proximal end portion243 of the needle 240 and the distal end portion 242 of the needle 240.The hub portion 244 serves as a transition area between the proximal endportion 243 of the needle and the distal end portion 242 of the needle.The hub portion 244 can be similar to a conical shape as shown in FIG. 6and includes a contact surface 245. The contact surface of the hubportion 245 is configured to make contact with the eye. In this mannerthe contact surface 245 can control the depth of penetration of thedistal end portion 242 and/or can form a fluidic seal with the surfaceof the eye.

The microneedle 240 defines a lumen 241. The lumen 241 of themicroneedle 240 can be of any suitable size or diameter. Moreparticularly the portion of the lumen within the proximal end portion243 is characterized by a first diameter d1 and the portion of the lumen241 within the distal end portion 242 is characterized by a seconddiameter d2 that is smaller than the first diameter. Similarly stated,the microneedle 240 has a spatially varying inner diameter. The typicaldiameter range for d1 is between 0.072 inches (15 gauge needle size) and0.083 inches (14 gauge needle size). In some embodiments, the diameterd1 can be any size larger than about 0.072 inches (15 gauge needlesize). In other embodiments, the diameter d1 can be any size larger thanabout 0.03575 inches (20 gauge needle size). In other yet embodiments,the diameter d1 can be any size larger than about 0.01625 inches (27gauge needle size). The diameter d2 can range between about 0.00825inches (33 gauge needle size) and 0.01225 inches (30 gauge needle size).In some embodiments, the diameter d2 can be any size smaller than about0.01225 inches (30 gauge needle size). In some embodiments, however, thediameter d2 can be any size smaller than about 0.01625 inches (27 gaugeneedle size). In this manner, the length of the smaller diameter portion(i.e., the distal end portion 242) can be minimized to reduce thefrictional losses associated with conveying the medicament through themicroneedle 240.

The portion of the lumen within the proximal end portion 243 ischaracterized by a length L1 and the portion of the lumen 241 within thedistal end portion 242 is characterized by a second length L2 that issmaller than the first length. The length L1 of the proximal end portion243 of the microneedle 240 can be about 0.300 inches. The length L2 ofthe distal end portion 242 of the microneedle 240 can be about 0.650inches. In other embodiments, the length of the distal end portion canbe any suitable amount to facilitate targeted injection into aparticular region when the transition (or hub) portion 245 is in contactwith the target tissue. For example, in some embodiments, the length L2of the distal end portion 242 of the microneedle 240 (or any of theneedles described herein) can be between about 200 microns and about1500 microns. In other embodiments, the length L2 of the distal endportion 242 of the microneedle 240 (or any of the needles describedherein) can be between about 900 microns and about 1100 microns. Byreducing the length of the smaller diameter portion of the microneedle240, the force requirement to produce a desired injection can beminimized.

In addition to the reduction in the frictional losses, the reducedlength of the smaller diameter portion also improves the mechanicalintegrity of the microneedle. In particular, the reduced length L2 canincrease the buckling resistance of the distal end portion 242. This, inturn, can allow the wall thickness of the distal end portion 242 to bedecreased.

The needles 140 and 240 described herein can be used in conjunction witha hub and injector. For example, any of the needles described herein canbe used in conjunction with any of the devices shown and described inInternational Patent Application No. PCT/US2015/036299, filed on Jun.17, 2015, entitled “Methods and Devices for Treating Posterior OcularDisorders,” which is incorporated herein by reference in its entirety.Additionally, FIG. 7 is a perspective view of a medical injector 300configured for use with the needles described herein, according to anembodiment. The medical injector 300 includes a handle 350, a medicamentcontainer 330, an actuator 320 (shown in FIG. 8), and a needle assembly360. The needle assembly 360 includes a hub 370 and a needle 340. Theneedle 340 can be a microneedle. The medical injector 300 can beconfigured to deliver a medicament to a region and/or a layer of atarget location, for example, an eye of a patient, (e.g., to the SCS ofthe eye), as described herein.

FIG. 8 is an exploded view of the medical injector of FIG. 7 in aconfiguration where the medical injector is not attached to a needleassembly, according to an embodiment. The handle 350 includes a firstportion 352 and a second portion 354, that can be coupled together todefine an internal region for housing at least a portion of themedicament container 330 and/or the actuator 320. The first portion 352and the second portion 354 of the handle 350 can be removably or fixedlycoupled together using any suitable means, for example, screws, nuts,bolts, rivets, adhesives, a snap-fit mechanism, notches, grooves,indents, a lock, a latch, or any other suitable couple mechanism. Thehandle 350 includes a gripping portion 356. A plurality of protrusions(e.g., ribs) are disposed on the gripping portion 356 to allow a user toeasily grip the handle 350, for example, between the user's index and/ormiddle finger and thumb. In some embodiments, a plurality of ridges 332are disposed on an outer surface of the medicament container 330. Theridges 332 can provide an additional gripping surface for the user tosecurely hold the handle 350. For example, a user can grip the grippingportion 356 with a first hand and grip the ridges 332 with a second handto limit any unwanted movement of the handle 350 and for more finecontrol during injection of medicament disposed in the medicamentcontainer 330.

The first portion 352 and/or the second portion 354 of the handleinclude, in an interior region therein, an actuator engagement portion358. The actuator engagement portion 358 is configured to mount and/orretain a handle engagement portion 326 of the actuator 320, such that alinear translation of the handle 350 along a longitudinal axis of themedical injector 300 urges the actuator 320 to also translate along thelongitudinal axis relative to the medicament container 330. Similarlystated, a user can engage the handle 350 resulting in actuation of theactuator 320.

The actuator 320 includes the handle engagement portion 326 and aplunger portion 327 movably disposed within an internal volume definedby the medicament container 330. At least a portion of the actuator 320is slidably disposed in the internal volume defined by the medicamentcontainer 330. Thus, the actuator 320 can be displaced within theinternal volume defined by the medicament container 330 for drawing themedicament into and/or expelling the medicament from the internal volumedefined by the medicament container 320. As discussed above, the handleengagement portion 326 of the actuator 320 can be fixedly coupled to thehandle 350. Thus, any linear displacement of the handle 350 along thelongitudinal axis of the medical injector 300 also urges the actuator320 to slide within the internal volume of the medicament container 330.

The handle engagement portion 326 of the actuator 320 can be anysuitable size, shape, or configuration. For example, as shown in FIG. 8,the handle engagement portion 326 can define an opening configured toreceive at least a portion of the actuator engagement portion 358 of thehandle. In this manner, the handle 350 and a portion of the actuator 320can be fixedly and operably coupled to each other, and therebycollectively configured to transfer a force to the medicament container330 such that a fluid can be conveyed from the medicament container 330,as described in further detail herein.

The plunger portion 327 of the actuator can be coupled to and/or incontact with a plug 328 which is in fluidic communication with asubstance (e.g., a medicament such as, for example, VEGF, a VEGFinhibitor, a combination thereof, or any other medicament describedherein) disposed within an internal volume defined by the medicamentcontainer 330. The plunger portion 327 of the actuator is configured tobe displaced within the internal volume defined by the medicamentcontainer 330, for example, due to a force produced by a user, asdescribed herein. In this manner, the actuator 320 can displace the plug328 within the medicament container to draw in or expel the substance Mfrom the distal tip of the needle 340, as described herein. Thesidewalls of the plug 328 can be configured to contact the sidewalls ofthe medicament container 330 such that the plug 328 forms asubstantially fluid-tight seal with the side wall of the medicamentcontainer 330, for example, to prevent leakage of the substance M. Theplug 328 can be made of an inert and/or biocompatible material which isrigid but soft. Example materials include rubber, silicone, plastic,polymers, any other suitable material or combination thereof. In someembodiments, the plug 328 can be monolithically formed with the actuator320. Moreover, the plug 328 can have a size, shape and/or can beconstructed from a material such that movement of the actuator 320and/or plug within the medicament container 330 is limited when theforce applied is below a predetermined threshold. In this manner, theplug 328 and actuator 320, in conjunction with the entire medicalinjector 300 (e.g., the medicament container, the substance beinginjected and the like) are configured such that a force applied can besufficient to inject the medicament when a distal end portion of theneedle is disposed within a first region of the target tissue (e.g., asuprachoroidal space), but insufficient to inject the medicament whenthe distal end portion of the needle is disposed within a second regionof the target tissue.

The medicament container 330 defines an internal volume configured tohouse a medicament (e.g., triamcinolone acetonide, VEGF, VEGF inhibitor,or any other medicament described herein). The medicament container 330includes a delivery portion 334. The delivery portion 334 includesthreads 336 for coupling the delivery portion to a needle assembly 360.Although shown as threads 336, the delivery portion 334 can include anysuitable coupling feature configured for coupling the delivery portionwith the hub 370, for example, a luer connector, a snap-fit, a latch, alock, a friction fit coupling, or any other suitable coupling features.The medicament container can be the same as or similar to any of themedicament containers described in U.S. patent application Ser. No.14/268,687, entitled “Apparatus and Methods for Ocular Injection,” FiledMay 2, 2014, which is incorporated by reference herein in its entirety.

As shown in FIGS. 9-10, the hub 370 includes an engagement portion 371,a coupling portion 372, and a delivery portion 373. An outer sidewall ofthe engagement portion 371 and an inner sidewall of the coupling portion372 define a recess 374 configured to receive the delivery portion 334of the medicament container 330. The inner sidewall of the couplingportion 372 includes threads 375 configured to engage the threads 336 ofthe medicament container 330, thereby coupling the hub 370 to themedicament container 330. An outer sidewall of the coupling portion 372includes a set of ridges 376. The ridges 376 can facilitate a user togrip the hub 370, for example, for coupling or uncoupling the hub 370from the medicament container 330. The engagement portion 371 defines afirst fluidic channel 377 configured to engage a fluidic channel of themedicament container 330 and establish fluidic communication between themedicament container 330 and the hub 370. The delivery portion 373defines a second fluidic channel 378 configured to removably receive theneedle 340, for example, a microneedle (e.g., any suitable microneedledescribed herein). The needle 340 is configured to be disposed within atarget tissue, for example, ocular tissue and defines a lumen 341 suchthat the needle 340 is configured to establish fluidic communicationbetween the medicament container 330 and the portion of the user's body(e.g., the eye). In some embodiments, the needle 340 can be fixedlydisposed in the second fluidic channel 378. In some embodiments, theneedle 340 can be monolithically formed with the hub 370 such that thesecond fluidic channel 378 and the lumen of the needle 341 arecontinuously and/or seamlessly formed.

The needle 340 includes a proximal end portion 343, a distal end portion342, and a hub portion 344 and defines a lumen 341 therethrough.Although shown as having a beveled distal end surface with a sharp tip,the distal end portion 342 of the needle 340 alternatively can have ablunt end. The hub portion 344 of the needle 340 is disposed between theproximal end portion 343 of the needle 340 and the distal end portion342 of the needle 340. The hub portion 344 serves as a transition areabetween the proximal end portion 343 of the needle and the distal endportion 342 of the needle. The hub portion 344 can be similar to aconical shape as shown in FIG. 6. In some embodiments, the needle 340can have a sufficient length so that the hub portion 344 includes acontact surface (not shown) configured to make contact with the eye. Thelength the distal end portion 342 extends beyond the distal end surface381 of the hub 370 can be any suitable length, e.g., about 900 microns.In this manner, the contact surface can control the depth of penetrationof the distal end portion and/or can form a fluidic seal with thesurface of the eye.

The needle 340 defines a lumen 341. The lumen 341 of the needle 340 canbe of any suitable size or diameter. More particularly the portion ofthe lumen within the proximal end portion 343 is characterized by afirst diameter and the portion of the lumen 341 within the distal endportion 342 is characterized by a second diameter that is smaller thanthe first diameter. Similarly stated, the needle 340 has a spatiallyvarying inner diameter. The typical diameter range for the firstdiameter is between about 0.072 inches (15 gauge needle size) and about0.083 inches (14 gauge needle size). In some embodiments, the firstdiameter can be any size larger than about 0.072 inches (15 gauge needlesize). In other embodiments, the first diameter can be any size largerthan about 0.03575 inches (20 gauge needle size). In other yetembodiments, the first diameter can be any size larger than about0.01625 inches (27 gauge needle size). The second diameter can rangebetween about 0.00825 inches (33 gauge needle size) and 0.01225 inches(30 gauge needle size). In some embodiments, the second diameter can beany size smaller than about 0.01225 inches (30 gauge needle size). Insome embodiments, however, the second diameter can be any size smallerthan about 0.01625 inches (27 gauge needle size). In this manner, thelength of the smaller diameter portion (i.e., the distal end portion)can be minimized to reduce the frictional losses associated withconveying the medicament through the microneedle 340.

The portion of the lumen within the proximal end portion 343 ischaracterized by a first length and the portion of the lumen 341 withinthe distal end portion 342 is characterized by a second length that issmaller than the first length. The first length of the proximal endportion 343 of the needle 340 can be about 0.300 inches. The secondlength of the distal end portion 342 of the needle 340 can be about0.650 inches. In other embodiments, the length of the distal end portioncan be any suitable amount to facilitate targeted injection into aparticular region when the transition (or hub) portion of the needle orthe distal surface of the hub is in contact with the target tissue. Forexample, in some embodiments, the length of the distal end portion 342of the microneedle 340 (or any of the needles described herein) can bebetween about 200 microns and about 1500 microns. In other embodiments,the length of the distal end portion 342 of the microneedle 340 (or anyof the needles described herein) can be between about 900 microns andabout 1100 microns. By reducing the length of the small-diameter portionof the needle 340, the force requirement to produce a desired injectioncan be minimized.

In addition reducing the frictional losses by reducing the length of thesmaller diameter portion, the reduced length also improves themechanical integrity of the needle. In particular, the reduced secondlength can increase the buckling resistance of the distal end portion342. This, in turn, can allow the wall thickness of the distal endportion 342 to be decreased.

As shown in FIG. 10, the hub 370 is configured to be physically andfluidically coupled to the needle 340 such that a fluid flow path isdefined therebetween. For example, the lumen 341 of the needle 340 isplaced in fluid communication with the first fluidic channel 377 and thesecond fluidic channel 378 of the hub 370 when the needle 340 isphysically and fluidically coupled within the second fluidic channel378. The distal end portion 342 of the needle 340 extends distally fromthe distal end surface 381 of the hub 370. The hub 370 can be anysuitable shape, size, and/or configuration. For example, in someembodiments, the hub 370 can define an inner volume that can house,store, or otherwise contain a therapeutic agent. In other embodiments,the hub 370 can be configured to receive a cartridge (not shown) thatcontainer a drug formulation (e.g., a prophylactic agent, a therapeuticagent, and/or a diagnostic agent). The distal end surface 381 of the hub370 can be substantially convex or curved to allow the distal endsurface to conform to a target tissue (e.g., an ocular tissue).Furthermore, the distal end surface 381 can define a sealing surfaceconfigured to form a substantially fluid tight seal with a targettissue, for example, ocular tissue (e.g., the conjunctiva or the sclera)when the distal end surface 381 of the hub 370 is pushed against theocular tissue (e.g., the conjunctiva or the sclera) as described herein.The distal end surface of the hub can include a sealing portionconfigured to define a substantially fluid-tight seal with the targetsurface. The sealing portion can surround a centerline of the needle.While shown as including the hub 370, the apparatus can include anysuitable rigid hub. The hub 370 can be formed from a relatively rigidmaterial such as a metal or hard plastic. The hub 370 can be the same orsimilar to any of the hubs described in U.S. patent application Ser. No.14/268,687, entitlted “Apparatus and Methods for Ocular Injection,”Filed May 2, 3014, which is incorporated by reference herein in itsentirety.

The hub 370 can be formed as a monolithic structure, as shown in FIG.10. Alternatively, in some embodiments, the hub can be formed fromseparate portions coupled together to form the hub 370. For example,FIGS. 11A-11C show a needle assembly 460 according to an embodiment.FIG. 11A is an exploded view of the needle assembly 460. The needleassembly 460 includes a hub 470 and a needle 440. The hub 470 has afirst portion 479 and a second portion 480. The first portion 479 andthe second portion 480 can be formed separately and coupled together.The first portion 479 and the second portion 480 can be coupled togetherthrough welding, the application of an adhesive, or any other suitablemeans. As shown in FIG. 11A, the second portion 480 can be securelyattached to the needle 440 before being coupled to the first portion479. The needle 440 can be a variable diameter cannula as described withreference to needles 140, 240, and 340 above.

FIG. 11B is a side view of the needle assembly 460 in an assembledconfiguration where the first portion 479 has been coupled to the secondportion 480. The hub 470 has a distal end surface 481 that is configuredto contact a target surface of a target tissue. The target tissue can befor example, an eye, and the target surface can be, for example, aconjunctiva of the eye or a sclera of the eye. The distal end surface ofthe hub can include a sealing portion configured to define asubstantially fluid-tight seal with the target surface. The sealingportion can surround a centerline of the needle 440.

FIG. 11C is a cross-sectional view of the needle assembly 460 takenalong line C-C in FIG. 11B. The first portion 479 of the hub 470 caninclude threads 475 to couple the needle assembly 460 to a medicamentcontainer. Although shown as threads 475, the hub 470 can include anysuitable coupling feature configured for coupling the hub 470 with amedicament container, for example, a luer connector, a snap-fit, alatch, a lock, a friction fit coupling, or any other suitable couplingfeatures.

The needle 440 can include any suitable needle as described herein, forexample, a microneedle (e.g., a 27 gauge, 30 gauge, or even smallerneedle). The needle 440 can have multiple different diameters. Further,the needle 440 can have any suitable length, e.g., a fixed length ofabout 900 μm or about 1100 μm, or any length therebetween. Additionally,the lengths of the distal end portion 442 and the proximal end portions443 can be any suitable length. For example, if the inner diameter ofthe distal end portion 442 is 30 gauge or smaller, a length of thedistal end portion 442 can be such that the medicament is conveyedthrough the lumen 441 when a force of less than about 6 N is exerted onan actuation rod. Additionally, the length of the distal end portion 442of the needle 440 can be less than the overall length of the needle 440.Similarly, the length that the distal end portion 442 extends beyond thedistal end surface 481 of the hub 470 can be any suitable length, e.g.,about 900 microns. The distal tip of the needle 440 can define a sharpand/or beveled tip such that the needle 440 is configured to pierce atarget location, for example, a bodily tissue (e.g., ocular tissue). Inthis manner, the distal tip can be disposed within a first region and/ora second region of the target location, as described herein. The needle440 defines a lumen 441, which is configured to be in fluidiccommunication with a substance disposed within an internal volumedefined by a medicament container and/or an internal volume 482 definedby the hub 470. In this manner, the needle 440 is configured toestablish fluid communication between the medicament container and thetarget location, for example, the first region of the target location,as described herein. In some embodiments, the first region of the targetlocation can have a first density and the second region can have asecond density, which is higher than the first density. In someembodiments, the first region of the target location produces a firstbackpressure on the distal tip of the needle, and the second regionproduces a second backpressure on the distal tip of the needle, which ishigher than the first backpressure. In other words, the first region ofthe target location produces a first pressure that resists and/oropposes flow from the distal tip of the needle, and the second regionproduces a second pressure that resists and/or opposes flow from thedistal tip of the needle, which is higher than the first pressure. Insome embodiments, the target location can be an eye such that the firstregion is a suprachoroidal space of the eye, and the second region is asclera of the eye.

Although shown as being a fixed needle, in some embodiments, such as theembodiments shown in FIGS. 12-17, the needle assembly can move relativeto the medicament container to have variable needle length. In someembodiments, an apparatus for injecting a medicament into a targettissue can include a medical injector and a hub with a compressiblemember disposed therebetween. The compressible member is configured tocompress and/or deform in response to a force to allow adjustment of alength of a needle. Similarly stated, the compressible member can deformto allow the length of the needle to extend distally from the hub to beadjusted. This arrangement can allow, for example, the adjustment of adistance the needle penetrates into a target tissue (i.e., the insertiondepth of the needle), for example, an ocular tissue. Referring now toFIGS. 12-15, an apparatus 500 includes a medical injector 510, a hub570, and a compressible member 578. The medical injector 510 includes anactuator rod 520, a medicament container 530, and a needle 540. Whileshown as including the medical injector 510, the apparatus 500 caninclude any other suitable medical injector. Examples of medicalinjectors which can be used in the apparatus 500 are described in U.S.patent application Ser. No. 14/268,687, now U.S. Patent Publication No.2015/0038905 (also referred to herein as “the '687 application”), filedMay 2, 2014, and entitled “Apparatus and Methods for Ocular Injection,”the disclosure of which is incorporated by reference herein in itsentirety.

The needle 540 can be any suitable puncture member configured topuncture a target tissue of the types shown and described herein. Forexample, the needle 540 can be a microneedle configured to punctureocular tissue. In some embodiments, the needle 540 can be a 30 gaugemicroneedle, a 32 gauge microneedle or a 34 gauge microneedle (or anysize within the range of about 30 gauge to about 34 gauge). In someembodiments, such a microneedle can be substantially similar to or thesame as the puncture members and microneedles described in the '009 PCTapplication incorporated by reference above. In some embodiments, theshape and/or size of the needle 540 can correspond, at least partially,with at least a portion of a target tissue. For example, in someembodiments, the length of the needle 540 can correspond with athickness of a portion of ocular tissue such that when the needle 540 isinserted into the ocular tissue, at least a portion of the needle 540 isdisposed within the sclera or suprachoroidal space of the eye, asdescribed in further detail herein. Moreover, as described herein, theexposed length of the needle can be adjusted. The needle 540 defines alumen 541 that extends through a proximal end 543 and a distal end 542of the needle 540. The distal end 542 of the needle 540 can include abevel or a sharpened tip configured to puncture a target tissue. Atleast a portion of the proximal end 543 of the needle 540 can bedisposed in a first passageway 576 defined by the hub 570 and a secondpassageway 579 defined by the compressible member 578, as describedherein.

The medicament container 530 of the medical injector 510 has a proximalend portion 532 and a distal end portion 534. The medicament container530 defines an inner volume 536 that can store, house, and/or otherwisecontain a substance (e.g., a medicament, a prophylactic agent, atherapeutic agent, and/or a diagnostic agent). For example, in someembodiments, a cartridge or the like containing a drug formulation or amedicament (e.g., a VEGF, a VEGF inhibitor, triamcinolone acetonide, anyother medicament described herein, or a combination thereof) can bedisposed within the inner volume 536 of the medicament container 530. Inother embodiments, a drug formulation can be disposed directly withinthe inner volume 536 (e.g., without a cartridge or other intermediatereservoir). In some embodiments, the inner volume 536 can contain a drugformulation with a volume of about 0.5 mL or less. In other embodiments,the inner volume 536 can contain a drug formulation with a volume ofabout 0.1 mL. In still other embodiments, the inner volume 536 cancontain a drug formulation with a volume greater than about 0.5 mL. Insome embodiments, the medicament container 530 can be substantiallysimilar to any medicament container described in the '687 application.

The proximal end portion 532 of the medicament container 530 issubstantially open to receive the actuation rod 520. More specifically,a distal end portion 524 of the actuation rod 520 is disposed within theinner volume 536 and can be moved between a first position (e.g., aproximal position) and a second position (e.g., a distal position). Saidanother way, the distal end portion 524 of the actuation rod 520 canmove an injection distance within the inner volume 536. A sealing membersuch as, for example, a plug or elastomeric member can be coupled toand/or moved by the distal end portion 524 of the actuation rod 520. Thesealing member can be configured to form a friction fit with one or moresurfaces of the medicament container 530 that define the inner volume536. In this manner, the sealing member and the medicament container 530can form a substantially fluid-tight seal that substantially isolates aportion of the inner volume 536 that is distal to the seal member from aportion of the inner volume 536 that is proximal to the sealing member.Said another way, the medicament container 530 and the actuation rod 520form at least a portion of a syringe.

The distal end portion of the medicament container 530 is coupled tocompressible member 578 and the hub 570 such that the compressiblemember 578 is disposed between the hub 570 and the distal end portion534 of the medicament container 530. As described in more detail below,the compressible member 578 and the hub 570 can be coupled to themedicament container 530 in any suitable manner. For example, in someembodiments, the compressible member 578 and/or the hub 570 can be asingle assembly that includes a luer fitting configured to be coupled toa corresponding tapered portion of the medicament container 530 (whichcan be, for example, a prefilled syringe). In other embodiments, thecompressible member 578 and the hub 570 can be separately constructedand/or separately coupled to the medicament container by an adhesive,threaded fitting or any other suitable mechanism.

The hub 570 defines a first passageway 576 configured to receive theneedle 540 therethrough such that the distal end 542 of the needleextends the substantially the length of the first passageway 576, andcan extend past a distal end surface 575 of the hub 570. The distal endsurface 575 of the hub 570 can be substantially convex or curved toallow the distal end surface to conform to a target tissue (e.g., anocular tissue). Furthermore, the distal end surface 575 can define asealing surface configured to form a substantially fluid tight seal witha target tissue, for example, ocular tissue (e.g., the conjunctiva) whenthe distal end surface 575 of the hub 570 is pushed against the oculartissue (e.g., the conjunctiva), as described herein. The sealing surface575 can surround a centerline of the needle 540. While shown asincluding the hub 570, the apparatus 500 can include any suitable rigidhub. Examples of hubs that can be used with the apparatus 500 aredescribed in the '687 application. The hub 570 can be formed from arelatively rigid material such as a metal or hard plastic.

The compressible member 578 is disposed between the medicament container530 and the hub 570, and is configured to compress. Similarly stated,the compressible member 578 is formulated and/or constructed toexperience a reduction in thickness in response to a force exerted onthe medical injector 510, and an opposite force exerted by the hub 570,as described herein. The compressible member 578 defines a secondpassageway 579 configured to receive at least a portion of the proximalend 543 of the needle 540. The second passageway 579 of the compressiblemember 578 is in communication with and/or aligned with the firstpassageway 576 of the hub 570 such that the needle 540 is disposedthrough the first passageway 576 and the second passageway 579. Thecompressible member 578 can be formed from a substantially compressiblematerial such as, for example, rubber, silicone, hydrogels, sol-gels,foam, sponge, aerogels, a non-linear elastic material, any othercompressible material or a combination thereof. In some embodiments, thecompressible member 578 can include a spring such as, for example,helical, compression, extension, spring washers, Belleville washers,tapered, any other type of spring, or any other suitable biasing member.The distal end portion 542 of the needle extends distally from thedistal end surface 575 of the hub 570 by a first length when thecompressible member 578 has a first thickness and by a second lengthwhen the compressible member 578 has a second thickness. The secondlength can be about 900 microns and about 1100 microns.

In some embodiments, the maximum reduction in thickness that thecompressible member 578 can undergo in response to a predetermined force(e.g., in the range of about 0.5 N to about 6 N, and more particularlyin the range of about 0.5 N to about 2 N) exerted on the medicalinjector 510 can be configured to correspond to a maximum insertiondepth of the distal end 542 of the needle 540 into a target tissue(e.g., ocular tissue). For example, in some embodiments, thecompressible member 578 can be configured to experience a maximumreduction in thickness of about 900 μm to about 1,200 μm in response toa force in the range of about 0.5 N to about 6 N exerted on the proximalend portion 522 of the actuation rod 520. In other embodiments, thecompressible member 578 can be configured to experience a maximumreduction in thickness of about 900 μm to about 1,200 μm in response toa force in the range of about 0.5 N to about 2 N exerted on the proximalend portion 522 of the actuation rod 520. In other embodiments, thecompressible member 578 can be configured to experience a maximumreduction in thickness of about 300 μm in response to a force in therange of less than about 6 N. This deformation and/or reduction inthickness allows the hub 570 to move proximally relative to themedicament container 530 a distance of about 900 μm to about 1,200 μm,thus exposing the distal end 542 of the needle 540 from the distal endsurface 575 of the hub 570 by the same or similar distance. In thismanner, the maximum depth the distal end 542 of the needle 540 can beinserted into a target tissue (e.g., an ocular tissue) or otherwise theinsertion depth of the needle 540 can be controlled. In someembodiments, the ratio of the thickness of the compressible member 578and the insertion depth of the needle 540 can be configured such thatthe distal end 542 of the needle 540 can be inserted to a desired depthin a target tissue (e.g., within or near the suprachoroidal space ofocular tissue) when a predetermined force, for example, in the range ofabout 0.5 N to about 6 N (or more particularly, the range of about 0.5 Nto about 2 N) is applied on the medical injector 510, as describedherein.

The compressible member 578 can have any shape or size. For example, thecompressible member 578 can include a circular disc, a rectangular disc,a square disc, a ring, multiple pieces of compressible material disposedbetween the hub 570 and the medicament container 530, or any othersuitable shape or size. The compressible member 578 can be coupled to adistal end surface of the medicament container 530 by any suitablemechanism. In some embodiments, the compressible member 578 can becoupled to the medicament container 530 and the hub 570 using, forexample, adhesives, hot welding, fusion bonding, screws, nuts, bolts,rivets, any other suitable coupling mechanism or combination thereof. Inother embodiments, an adapter (e.g., a luer adapter, a collar or thelike) or any other piece can be disposed between the hub 570 and themedicament container 530, and can function to couple the compressiblemember 578 to the medicament container 530.

As described herein, the apparatus 500 can be used to control theinsertion depth of a distal end 542 of the needle 540 into a targettissue, for example, an ocular tissue. In this manner, the apparatus 500can be used to move (or guide the movement of) the distal end 542 of theneedle 540 to a desired depth in a target tissue to enable delivery ofthe medicament to a target location of the target tissue (e.g., thesuprachoroidal space of ocular tissue). For example, in someembodiments, the apparatus 500 can be configured to deliver a medicamentto the suprachoroidal space of the eye. FIG. 13 shows a portion of theapparatus 500 that includes the hub 570 and the compressible member 578in a first configuration. In the first configuration, the distal endsurface 575 of the hub 570 can be disposed on and in contact with theconjunctiva C of an eye. As described herein, the hub 570 is formed froma rigid material such that the distal end surface 575 is configured toform a substantially fluid tight seal with the conjunctiva C of the eye.Furthermore, in the first configuration, the compressible member 578 isuncompressed and has a first thickness t₁. The first thickness t₁ issuch that in the first configuration, the distal end 542 of the needle540 is disposed within the hub 570 (i.e., the distal end 542 of theneedle 540 does not protrude beyond the distal end surface 575 of thehub 570). In this manner, for example, the hub 570 and the compressiblemember 578 can serve as a safety mechanism to prevent accidentalpuncturing or otherwise sticking by the distal end 542 of the needle 540both before and after use.

In the second configuration, as shown in FIG. 14, a force in a directionshown by the arrow F can be exerted on the apparatus 500, for example,on the proximal end portion 522 of the actuation rod 520. Alternatively,the force F can be applied directly to the medicament container 530. Asshown, the force F can urge the distal end surface 575 of the hub 570 topress against the conjunctiva C. Since the hub 570 is a substantiallyrigid member that has a stiffness substantially greater than thestiffness of the conjunctiva C (e.g., a stiffness substantially similarto a stiffness of stainless steel), application of the force F deformsthe conjunctiva C, without causing substantial deformation of the hub570. The magnitude of the force F can be insufficient to depress thedistal end surface 575 of the hub 570 any further into the conjunctivaC. For example, it is known that practitioners generally prefer to limitthe manual force applied to the eye within the range of about 0.5 N toabout 6 N (or more particularly, within the range of about 0.5 N toabout 2 N). Thus, the hub 570 and the compressible member 578 can beconfigured to deform and/or respond to the Force within this range tofacilitate the desired penetration of the needle 540. In particular, theforce F can be sufficient to compress the compressible material 578 suchthat the compressible material 578 experiences a reduction in thicknessfor the first thickness t₁ to a second thickness t₂. This allows themedicament container 530 and/or needle 540 to move proximally relativeto the hub 570. This proximal movement urges the distal end 542 of theneedle 540 to also move proximally relative to the eye such that thedistal end 542 of the needle 540 pierces the conjunctiva C and isdisposed in the sclera S of the eye.

In a third configuration shown in FIG. 15, the force F can be maintainedsuch that the thickness of the compressible member reduces to a thirdthickness t₃. This further reduction in the thickness of thecompressible member 578 allows the distal end 542 of the needle 540 toprotrude further into the eye until the distal end 542 is disposed in asuprachoroidal space SCS (e.g., the target layer) of the eye but doesnot pierce further into the eye (e.g., the retina R, the vitreous orother layers). When the device 500 is in the third configuration, themedicament can be injected into the suprachoroidal space SCS, eithermanually or using an injection assist assembly examples of which aredescribed in the '687 application. In some embodiments, the thicknessand/or the compressibility (or otherwise stiffness coefficient) of thecompressible member 578 can be configured such that the thickness of thecompressible material 578 cannot easily be reduced to a thickness lessthan t₃. In this manner, the compressible member 578 can control and/orlimit the insertion depth of the distal end 542 of the needle 542, forexample, to be in the range of about 900 μm to about 1,200 μm. Thisdistance can be sufficient to allow the distal end 542 of the needle 540to be inserted to the suprachoroidal space SCS of the eye but canprevent any travel of the distal end 542 of the needle 540 beyond thesuprachoroidal space SCS into the retina R. Thus, the compressiblemember 578 can also serve as a stopping mechanism to control theinsertion depth of the distal tip 542 of the needle 540 to be within adesired range.

For example, in some embodiments, the compressible member 578 can beconstructed from a material (or combination of materials) such that therate of deformation is non-linear. In particular, the rate ofdeformation can decrease when the force F exceeds a certain threshold(e.g., 6 N), thereby limiting any further deformation. In someembodiments, for example, the compressible member 578 can be a compositearticle constructed from layers of different materials.

Although the hub 570 is described above as being substantially stiff(and non-deformable), in some embodiments, the hub 570 can have astiffness that is intermediate to the stiffness of the conjunctiva C andthe sclera S. In such embodiments, application of the force F can urgethe hub 570 to deform the conjunctiva C until the distal end surface 575of the hub 570 is proximate to the sclera S. Since the stiffness of thehub 570 is less than the stiffness of the sclera S, further applicationof the force F will urge the distal end surface 575 of the hub 570 todeform without any substantial deformation of the sclera S. In thismanner, the hub 570 can prevent application of an excessive force fromcausing damage to or otherwise deformation and/or piercing of theinternal layers of the eye.

Although the compressible member 578 is described above as optionallybeing configured to limit its deformation, in some embodiments, anapparatus can include a stopping mechanism to stop or otherwise limitcompression of a compressible member to define a maximum insertion depthof a distal end of a needle into a target tissue. Referring now to FIGS.16 and 17, an apparatus 600 includes a medical injector 610, a needle640, a hub 670, a compressible member 678, and a stopping mechanism 680.The medical injector 610 includes a medicament container 630, and anactuator (not shown). The medical injector 610 can be substantiallysimilar to the medical injector 510 and is therefore, not described infurther detail herein.

The hub 670 and the compressible member 678 can be substantially similarto hub 570 and the compressible member 578, respectively described withrespect to the apparatus 500. The stopping mechanism 680 includes abackstop 681, and a set of stoppers 682. A distal end portion of themedicament container 630 is coupled to the backstop 681 such that thebackstop 681 is disposed between the medicament container 630 and thecompressible member 678. The backstop 681 can be formed a substantiallyrigid material such as, for example, metals, or plastic. In someembodiments, the backstop 681 can be fixedly coupled to the distal endportion of the medicament container 630 and/or the compressible member,for example, with adhesives, hot welding, fusion bonding, screws, nuts,bolts, rivets, and the likes. In some embodiments, the backstop 681 canbe monolithically formed with the medicament container 630. The backstop681 defines a bore 683 within which at least a portion of a proximal end643 of the needle 640 is disposed.

The stoppers 682 can includes rods or otherwise protrusions. A distalend portion of each of the stoppers 682 is fixedly coupled to the hub670. For example, the distal end portion of the stoppers 682 can bedisposed within cavities defined by the hub 670, screwed, snap-fitted,press-fitted, friction-fitted, fixedly coupled to the hub 670 usingadhesives, hot welding, fusion bonding, or any other suitable couplingmechanism. In some embodiments, the stoppers 682 can be monolithicallyformed with the hub 670. The stoppers 682 can be formed from asubstantially rigid material such as, for example, metals or plastics.At least a portion of each of the stoppers 682 is disposed withinthroughholes defined within the compressible member 678 such that thestoppers 682 extend through the compressible member 678. Thus, thestoppers 682 are free to slide, move or otherwise displace with thethroughholes defined by the compressible member 678. A proximal endportion of each of the stoppers 682 is disposed within a correspondingchannel from set of channels 684 defined by the backstop 681 such thatthe proximal end portion of the stoppers 682 is free to slide within thechannels 684. In some embodiments, a protrusion 685 can be disposed onthe proximal end portion of the stopper 682. The protrusion 685 can, forexample, be configured to interact with a set of grooves or notchesdefined in the corresponding channel 684 to allow displacement of theprotrusions 685 within the channels 684 in fixed or otherwisepredetermined increments. In this manner, the protrusions 685 can allowthe compressible member 678 to experience a reduction in thickness, andthe hub 670 to move proximally relative to the medicament container 630in fixed increments. Furthermore, the channels 684 can have apredetermined length to allow displacement of the proximal end portionof the stoppers 682 until the distal end portion of the stoppers 682contacts a back wall 686 of the channel 685. In this manner, thechannels 684 and/or the backstop 681 can limit the displacement of thedistal end portion of the stoppers 682 proximally relative to themedicament container 630 and thereby, define the maximum length that adistal end 642 of the needle 640 can emerge from a distal end surface675 of the hub 670. Said another way, the length of the channels 684defined by the backstop 681 can be configured to define the maximuminsertion depth of the distal end 642 of the needle 640 in a targettissue (e.g., ocular tissue).

Expanding further, FIG. 16 shows the apparatus 600 in a firstconfiguration. In the first configuration, the distal end surface 675 ofthe hub 670 can be disposed against a conjunctiva C of ocular tissue.Furthermore, the compressible member 678 is uncompressed and defines afirst thickness t₄. A distal end 642 of the needle 640 is disposedwithin a first passageway 676 defined by the hub 670 such that a distaltip of the needle 640 is disposed within the first passageway 676 anddoes not protrude beyond a distal end surface 675 of the hub 670. Atleast a portion of the proximal end 643 of the needle 640 is disposedwithin the bore 683 defined by the backstop 681 and passes through asecond passageway 679 defined by the compressible member 678. The needle640 defines a lumen 641 therethrough configured to deliver a substance,for example, a medicament disposed within the medicament chamber 630 toa target location in the ocular tissue, for example, the suprachoroidalspace SCS. The proximal end portion of each of the stoppers 682 isdisposed within the corresponding channel 684 defined by the backstop681 such that the proximal ends of the stoppers 682 are distal to theback wall 686 of the channels 684.

A user can exert a force in the direction shown by the arrow F on themedical injector 610 to urge the apparatus into a second configuration,as shown in FIG. 17. The distal end surface 675 of the hub 670 can pressagainst the conjunctiva and form a substantially fluid tight seal withthe conjunctiva C, as described herein. Any further movement of the hub670 however, is prevented by the conjunctiva C and/or the underlyingocular tissue. Maintaining or increasing the magnitude of the force Fcan urge the medical injector 610 and thereby the medicament container630 and/or the needle 640 to move proximally relative to the hub 670.This urges the distal end 642 of the needle 640 to pierce through theconjunctiva C and into the sclera S of the eye. This also urges thestoppers 682 to move proximally relative to the hub 670 within thechannels 684. The force F compresses the compressible member 678 betweenthe rigid backstop 681 and the rigid hub 670. As shown in FIG. 17, theforce F can be maintained until the back wall 686 contacts the proximalend of the stoppers 682 and the compressible member is compressed to asecond thickness t₅. Any further reduction in thickness of thecompressible member 678 is prevented by the contact of the back wall 686with the proximal end of the stoppers 682. In this manner, the stoppingmechanism 680 can define the maximum reduction in thickness that thecompressible member 678 can experience, and thereby the maximum distancethe distal end 642 of the needle 640 can protrude into the eye, i.e.,the maximum insertion depth of the distal end 642 of the needle 640. Forexample, the stopping mechanism 680 can be configured to limit themaximum insertion depth of the distal end 642 of the needle 640 to thesuprachoroidal space SCS (e.g., about 900 μum to about 1,200 μm) andprevent insertion of the distal end 642 of the needle 640 into theretina R of the eye.

The embodiments described herein can be formed or constructed of one ormore biocompatible materials. Examples of suitable biocompatiblematerials include metals, glasses, ceramics, or polymers. Examples ofsuitable metals include pharmaceutical grade stainless steel, gold,titanium, nickel, iron, platinum, tin, chromium, copper, and alloysthereof. The polymer may be biodegradable or non-biodegradable. Examplesof suitable biodegradable polymers include polylactides, polyglycolides,polylactide-co-glycolides (PLGA), polyanhydrides, polyorthoesters,polyetheresters, polycaprolactones, polyesteramides, poly(butyric acid),poly(valeric acid), polyurethanes and copolymers and blends thereof.Examples of non-biodegradable polymers include nylons, polyesters,polycarbonates, polyacrylates, polymers of ethylene-vinyl acetates andother acyl substituted cellulose acetates, non-degradable polyurethanes,polystyrenes, polyvinyl chloride, polyvinyl fluoride, poly(vinylimidazole), chlorosulphonate polyolefins, polyethylene oxide, blends andcopolymers thereof.

The microneedles described herein can be fabricated by a variety ofmethods. For example, in some embodiments, the hollow microneedle isfabricated using a laser or similar optical energy source. In oneexample, a microcannula may be cut using a laser to represent thedesired microneedle length. The laser may also be used to shape singleor multiple tip openings. Single or multiple cuts may be performed on asingle microncannula to shape the desired microneedle structure. In oneexample, the microcannula may be made of metal such as stainless steeland cut using a laser with a wavelength in the infrared region of thelight spectrum (0.7-300 μm). Further refinement may be performed usingmetal electropolishing techniques familiar to those in the field. Inanother embodiment, the microneedle length and optional bevel is formedby a physical grinding process, which for example may include grinding ametal cannula against a moving abrasive surface. The fabrication processmay further include precision grinding, micro-bead jet blasting andultrasonic cleaning to form the shape of the desired precise tip of themicroneedle.

In some embodiments, a variable diameter needle of the types shown anddescribed herein (e.g., needle 240) can be fabricated by a deep drawingprocess. This process can be used to produce the monolithic needleshaving a variable diameter, as described herein. Moreover, the deepdrawing process can produce a needle having a thin wall thickness.

A wide range of ocular diseases and disorders may be treated by themethods and devices described herein. Non-limiting examples of oculardiseases include uveitis, glaucoma, diabetic macular edema orretinopathy, macular degeneration, retinoblastoma, and genetic diseases.The methods described herein are particularly useful for the localdelivery of drugs that need to be administered to the posterior regionof the eye, for example the retinochoroidal tissue, macula, and opticnerve in the posterior segment of the eye. In one embodiment, thedelivery methods and devices described herein may be used in gene-basedtherapy applications. For example, the methods may administer a fluiddrug formulation into the suprachoroidal space to deliver select DNA,RNA, or oligonucleotides to targeted ocular tissues.

The microneedles can be used to target delivery to specific tissues orregions within the eye or in neighboring tissue. In various embodiments,the methods may be designed for drug delivery specifically to thesclera, the choroid, the Bruch's membrane, the retinal pigmentepithelium, the subretinal space, the retina, the macula, the opticdisk, the optic nerve, the ciliary body, the trabecular meshwork, theaqueous humor, the vitreous humor, and other ocular tissue orneighboring tissue in need of treatment.

A wide range of drugs may be formulated for delivery to ocular tissuesusing the present systems and devices described herein. Moreover, any ofthe delivery devices and/or methods described herein can involve,include and/or contain any of the drugs described herein. For example,in some embodiments, the medicament container 130, 330, 530, 630, or anyother medicament container can contain any of the drugs and/orformulations described herein. As used herein, the term “drug” (or“medicament”) refers to any prophylactic, therapeutic, or diagnosticagent (e.g., a contrast agent). The drug may be selected from suitableproteins, peptides and fragments thereof, which can be naturallyoccurring, synthesized or recombinantly produced. Representativeexamples of types of drugs for delivery to ocular tissues includeantibodies, anti-viral agents, chemotherapeutic agents (e.g.,topoisomerase inhibitors), analgesics, anesthetics, aptamers,antihistamines, anti-inflammatory agents, and anti-neoplastic agents. Inone embodiment, the drug is triamcinolone or triamcinolone acetonide.

The “therapeutic formulation,” medicament, or drug delivered via themethods and devices provided herein in one embodiment, is an aqueoussolution or suspension, and comprises an effective amount of the drug ortherapeutic agent, for example, a cellular suspension. In someembodiments, the therapeutic formulation is a fluid drug formulation.The “drug formulation” is a formulation of a drug, which typicallyincludes one or more pharmaceutically acceptable excipient materialsknown in the art. The term “excipient” refers to any non-activeingredient of the formulation intended to facilitate handling,stability, dispersibility, wettability, release kinetics, and/orinjection of the drug. In one embodiment, the excipient may include orconsist of water or saline.

The therapeutic formulation delivered to the suprachoroidal space of theeye of a human subject for the treatment of uveitis (e.g.,non-infectious uveitis), macular edema associated with uveitis (e.g.,non-infectious uveitis), macular edema associated with RVO or wet AMD,may be in the form of a liquid drug, a liquid solution that includes adrug or therapy in a suitable solvent, or liquid suspension. The liquidsuspension may include microparticles or nanoparticles dispersed in asuitable liquid vehicle for infusion. In various embodiments, the drugis included in a liquid vehicle, in microparticles or nanoparticles, orin both the vehicle and particles. The drug formulation is sufficientlyfluid to flow into and within the suprachoroidal space, as well as intothe surrounding posterior ocular tissues. In one embodiment, theviscosity of the fluid drug formulation is about 1 cP at 37° C.

In one embodiment, the drug formulation (e.g., fluid drug formulation)includes microparticles or nanoparticles, either of which includes atleast one drug. Desirably, the microparticles or nanoparticles providefor the controlled release of drug into the suprachoroidal space andsurrounding posterior ocular tissue. As used herein, the term“microparticle” encompasses microspheres, microcapsules, microparticles,and beads, having a number average diameter of from about 1 μm to about100 μm, for example from about 1 to about 25 μm, or from about 1 μm toabout 7 μm. “Nanoparticles” are particles having an average diameter offrom about 1 nm to about 1000 nm. The microparticles, in one embodiment,have a D₅₀ of about 3 μm or less. In a further embodiment, the D₆₀ isabout 2 μm. In another embodiment, the D₅₀ of the particles in the drugformulation is about 2 μm or less. In another embodiment, the D₅₀ of theparticles in the drug formulation is about 1000 nm or less. In oneembodiment, the drug formulation comprises microparticles having a D₉₉of about 10 μm or less. The microparticles, in one embodiment, have aD₅₀ of about 3 μm or less. In a further embodiment, the D₅₀ is about 2μm. In another embodiment, the D50 of the particles in the drugformulation is about 2 μm or less. In another embodiment, the D50 of theparticles in the drug formulation is about 1000 nm or less. In oneembodiment, the drug formulation comprises microparticles having a D₉₉of about 10 μm or less. The microparticles, in one embodiment, have aD₅₀ of about 3 μm or less. In a further embodiment, the D₅₀ is about 2μm. In another embodiment, the D₅₀ of the particles in the drugformulation is about 2 μm or less. In another embodiment, the D₅₀ of theparticles in the drug formulation is about 100 nm to about 1000 nm. Inone embodiment, the drug formulation comprises microparticles having aD₉₉ of about 1000 nm to about 10 μm. The microparticles, in oneembodiment, have a D₅₀ of about 1 μm to about 5 μm or less. In anotherembodiment, the drug formulation comprises particles having a D₉₉ ofabout 10 μm. In another embodiment, the D₉₉ of the particles in theformulation is less than about 10 μm, or less than about 9 μm, or lessthan about 7 μm or less than about 3 μm. In a further embodiment, themicroparticles or nanoparticles comprise an anti-inflammatory drug. In afurther embodiment, the anti-inflammatory drug is triamcinolone.

Microparticles and nanoparticles may or may not be spherical in shape.“Microcapsules” and “nanocapsules” are defined as microparticles andnanoparticles having an outer shell surrounding a core of anothermaterial. The core can be liquid, gel, solid, gas, or a combinationthereof. In one case, the microcapsule or nanocapsule may be a“microbubble” or “nanobubble” having an outer shell surrounding a coreof gas, wherein the drug is disposed on the surface of the outer shell,in the outer shell itself, or in the core. (Microbubbles and nanobublesmay respond to acoustic vibrations as known in the art for diagnosis orto burst the microbubble to release its payload at/into a select oculartissue site.) “Microspheres” and “nanospheres” can be solid spheres, canbe porous and include a sponge-like or honeycomb structure formed bypores or voids in a matrix material or shell, or can include multiplediscrete voids in a matrix material or shell. The microparticles ornanoparticles may further include a matrix material. The shell or matrixmaterial may be a polymer, amino acid, saccharride, or other materialknown in the art of microencapsulation.

The drug-containing microparticles or nanoparticles may be suspended inan aqueous or non-aqueous liquid vehicle. The liquid vehicle may be apharmaceutically acceptable aqueous solution, and optionally may furtherinclude a surfactant. The microparticles or nanoparticles of drugthemselves may include an excipient material, such as a polymer, apolysaccharide, a surfactant, etc., which are known in the art tocontrol the kinetics of drug release from particles.

In one embodiment, the drug formulation further includes an agenteffective to degrade collagen or GAG fibers in the sclera, which mayenhance penetration/release of the drug into the ocular tissues. Thisagent may be, for example, an enzyme, such a hyaluronidase, acollagenase, or a combination thereof. In a variation of this method,the enzyme is administered to the ocular tissue in a separate stepfrom—preceding or following—infusion of the drug. The enzyme and drugare administered at the same site.

In another embodiment, the drug formulation is one which undergoes aphase change upon administration. For instance, a liquid drugformulation may be injected through hollow microneedles into thesuprachoroidal space, where it then gels and the drug diffuses out fromthe gel for controlled release.

The therapeutic substance in one embodiment is formulated with one ormore polymeric excipients to limit therapeutic substance migrationand/or to increase viscosity of the formulation. A polymeric excipientmay be selected and formulated to act as a viscous gel-like materialin-situ and thereby spread into a region of the suprachoroidal space anduniformly distribute and retain the drug. The polymer excipient in oneembodiment is selected and formulated to provide the appropriateviscosity, flow and dissolution properties. For example,carboxymethylcellulose is used in one embodiment to form a gel-likematerial in the suprachoroidal space. The viscosity of the polymer inone embodiment is enhanced by appropriate chemical modification to thepolymer to increase associative properties such as the addition ofhydrophobic moieties, the selection of higher molecular weight polymeror by formulation with appropriate surfactants.

The dissolution properties of the therapeutic formulation in oneembodiment is adjusted by tailoring of the water solubility, molecularweight, and concentration of the polymeric excipient in the range ofappropriate thixotropic properties to allow both delivery through asmall gauge needle and localization in the suprachoroidal space. Thepolymeric excipient may be formulated to increase in viscosity or tocross-link after delivery to further limit migration or dissolution ofthe material and incorporated drug.

Water soluble polymers that are physiologically compatible are suitablefor use as polymeric excipients in the therapeutic formulationsdescribed herein, and for delivery via the methods and devices describedherein include but are not limited to synthetic polymers such aspolyvinylalcohol, polyvinylpyrollidone, polyethylene glycol,polyethylene oxide, polyhydroxyethylmethacrylate, polypropylene glycoland propylene oxide, and biological polymers such as cellulosederivatives, chitin derivatives, alginate, gelatin, starch derivatives,hyaluronic acid, chondroiten sulfate, dermatin sulfate, and otherglycosoaminoglycans, and mixtures or copolymers of such polymers. Thepolymeric excipient is selected in one embodiment to allow dissolutionover time, with the rate controlled by the concentration, molecularweight, water solubility, crosslinking, enzyme lability and tissueadhesive properties of the polymer.

In one embodiment, a viscosity modifying agent is present in atherapeutic formulation delivered by one of the methods and/or devicesdescribed herein. In a further embodiment, the viscosity modifying agentis polyvinyl alcohol, polyvinyl pyrrolidone, methyl cellulose,hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxymethyl celluloseor hydroxypropyl cellulose. In another embodiment, the formulationcomprises a gelling agent such as poly(hydroxymethylmethacrylate,poly(N-vinylpyrrolidone), polyvinyl alcohol or an acrylic acid polymersuch as Carbopol.

In one embodiment, the therapeutic formulation is delivered via one ofthe methods and or devices described herein as a liposomal formulation,

Liposomes can be produced by a variety of methods. Bangham's procedure(J. Mol. Biol., J Mol Biol. 13(1):238-52, 1965) produces ordinarymultilamellar vesicles (MLVs). Lenk et al. (U.S. Pat. Nos. 4,522,803,5,030,453 and 5,169,637), Fountain et al. (U.S. Pat. No. 4,588,578) andCullis et al. (U.S. Pat. No. 4,975,282) disclose methods for producingmultilamellar liposomes having substantially equal interlamellar solutedistribution in each of their aqueous compartments. Paphadjopoulos etal., U.S. Pat. No. 4,235,871, discloses preparation of oligolamellarliposomes by reverse phase evaporation. Each of the patents referencesin this paragraph is incorporated by reference herein in theirentireties for all purposes.

In one embodiment, the liposomal formulation comprises a phosolipid. Ina further embodiment, the liposomal formulation comprises a sterol suchas cholesterol.

In another embodiment, the liposomal formulation comprises unilamellarvesiscles. Unilamellar vesicles can be produced from MLVs by a number oftechniques, for example, the extrusion of Cullis et al. (U.S. Pat. No.5,008,050) and Loughrey et al. (U.S. Pat. No. 5,059,421). Sonication andhomogenization can be used to produce smaller unilamellar liposomes fromlarger liposomes (see, for example, Paphadjopoulos et al., Biochim.Biophys. Acta., 135:624-638, 1967; Deamer, U.S. Pat. No. 4,515,736; andChapman et al., Liposome Technol., 1984, pp. 1-18). A review of theseand other methods for producing liposomes can be found in the textLiposomes, Marc Ostro, ed., Marcel Dekker, Inc., New York, 1983, Chapter1, the pertinent portions of which are incorporated herein by reference.See also Szoka, Jr. et al., (1980, Ann. Rev. Biophys. Bioeng., 9:467).Each of the references in this paragraph is incorporated by referenceherein in their entireties for all purposes.

The term “antibody” is intended to refer broadly to any immunologicbinding agent such as IgG, IgM, IgA, IgD and IgE. An antibody can bemonoclonal or polyclonal, and in one embodiment, is a humanizedantibody. The term “antibody” is also used to refer to any antibody-likemolecule that has an antigen binding region, and includes antibodyfragments such as Fab′, Fab, F(ab′)₂, single domain antibodies (DABs),Fv, scFv (single chain Fv), and engineering multivalent antibodyfragments such as dibodies, tribodies and multibodies. The techniquesfor preparing and using various antibody-based constructs and fragmentsare well known in the art (see, e.g., Antibodies: A Laboratory Manual,Cold Spring Harbor Laboratory, 1988; incorporated herein by reference).

Non-limiting examples of specific drugs and classes of drugs includeβ-adrenoceptor antagonists (e.g., carteolol, cetamolol, betaxolol,levobunolol, metipranolol, timolol), miotics (e.g., pilocarpine,carbachol, physostigmine), sympathomimetics (e.g., adrenaline,dipivefrine), carbonic anhydrase inhibitors (e.g., acetazolamide,dorzolamide), topoisomerase inhibitors (e.g., topotecan, irinotecan,camptothecin, lamellarin D, etoposide, teniposide, doxorubicin,mitoxantrone, amsacrine), prostaglandins, anti-microbial compounds,including anti-bacterials and anti-fungals (e.g., chloramphenicol,chlortetracycline, ciprofloxacin, framycetin, fusidic acid, gentamicin,neomycin, norfloxacin, ofloxacin, polymyxin, propamidine, tetracycline,tobramycin, quinolines), anti-viral compounds (e.g., acyclovir,cidofovir, idoxuridine, interferons), aldose reductase inhibitors,anti-inflammatory and/or anti-allergy compounds (e.g., steroidalcompounds such as betamethasone, clobetasone, dexamethasone,fluorometholone, hydrocortisone, prednisolone and non-steroidalcompounds such as antazoline, bromfenac, diclofenac, indomethacin,lodoxamide, saprofen, sodium cromoglycate), artificial tear/dry eyetherapies, local anesthetics (e.g., amethocaine, lignocaine,oxbuprocaine, proxymetacaine), cyclosporine, diclofenac, urogastrone andgrowth factors such as epidermal growth factor, mydriatics andcycloplegics, mitomycin C, and collagenase inhibitors and treatments ofage-related macular degeneration such as pegagtanib sodium, ranibizumab,aflibercept and bevacizumab.

In one embodiment, the drug is an integrin antagonist, a selectinantagonist, an adhesion molecule antagonist (e.g., intercellularadhesion molecule (ICAM)-1, ICAM-2, ICAM-3, platelet endothelialadhesion molecule (PCAM), vascular cell adhesion molecule (VCAM)), aleukocyte adhesion-inducing cytokine or growth factor antagonist (e.g.,tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), monocytechemotatic protein-1 (MCP-1), or a vascular endothelial growth factor(VEGF)). In some embodiments, a vascular endothelial growth factor(VEGF) inhibitor is administered with one of the microneedles describedherein. In some embodiments, two drugs are delivered by the methodsdescribed herein. The compounds may be administered in one formulation,or administered serially, in two separate formulations. For example,both a VEGF inhibitor and VEGF are provided. In some embodiments, theVEGF inhibitor is an antibody, for example a humanized monoclonalantibody. In further embodiments, the VEGF antibody is bevacizumab. Inanother embodiment, the VEGF inhibitor is ranibizumab, aflibercept orpegaptanib. In still other embodiments, the devices and methodsdescribed herein can be used to deliver one or more of the followingVEGF antagonists: AL8326, 2C3 antibody, AT001 antibody, HyBEV,bevacizumab (Avastin), ANG3070, APX003 antibody, APX004 antibody,ponatinib (AP24534), BDM-E, VGX100 antibody (VGX100 CIRCADIAN), VGX200(c-fos induced growth factor monoclonal antibody), VGX300, COSMIX,DLX903/1008 antibody, ENMD2076, Sutent (sunitinib malate), INDUS815C,R84 antibody, KD019, NM3, allogenic mesenchymal precursor cells combinedwith an anti-VEGF agent or antibody, MGCD265, MG516, VEGF-Receptorkinase inhibitors, MP0260, NT503, anti-DLL4/VEGF bispecific antibody,PAN90806, Palomid 529, BD0801 antibody, XV615, lucitanib (AL3810,E3810), AMG706 (motesanib diphosphate), AAV2-sFLT01, soluble Flt1receptor, Cediranib (Recentin), AV-951 (Tivozanib, KRN-951), Stivarga(regorafenib), Volasertib (BI6727), CEP11981, KH903, Lenvatinib (E7080),terameprocol (EM1421), ranibizumab (Lucentis), Votrient (pazopanibhydrochloride), PF00337210, PRS050, SP01 (curcumin),Carboxyamidotriazole orotate, hydroxychloroquine, linifanib (ABT869,RG3635), Iluvien (fluocinolone acetonide), ALG1001, AGN150998, DARPinMP0112, AMG386, ponatinib (AP24534), AVA101, Vargatef (nintedanib),BMS690514, KH902, golvatinib (E7050), Afinitor (everolimus), Dovitiniblactate (TKI258, CHIR258), ORA101, ORA102, Axitinib (Inlyta, AG013736),Plitidepsin (Aplidin), Lenvatinib mesylate, PTC299, aflibercept(Zaltrap, Eylea), pegaptanib sodium (Macugen, LI900015), Visudyne(verteporfin), bucillamine (Rimatil, Lamin, Brimani, Lamit, Boomiq), R3antibody, AT001/r84 antibody, troponin (BLS0597), EG3306, vatalanib(PTK787), Bmab100, GSK2136773, Anti-VEGFR Alterase, Avila, CEP7055,CLT009, ESBA903, HuMax-VEGF antibody, GW654652, HMPL010, GEM220, HYB676,JNJ17029259, TAK593, XtendVEGF antibody, Nova21012, Nova21013, CP564959,Smart Anti-VEGF antibody, AG028262, AG13958, CVX241, SU14813, PRS055,PG501, PG545, PTI101, TG100948, ICS283, XL647, enzastaurin hydrochloride(LY317615), BC194, quinolines, COT601M06.1, COT604M06.2, MabionVEGF,SIR-Spheres coupled to anti-VEGF or VEGF-R antibody, Apatinib (YN968D1),and AL3818. In addition, delivery of a VEGF inhibitor or VEGF antagonistusing the microneedle devices and methods disclosed herein may becombined with one or more agents listed herein or with other agentsknown in the art.

In one embodiment, delivery of a VEGF antagonist to the suprachoroidalspace of the eye using the devices and methods disclosed herein is usedto treat, prevent and/or ameliorate a disease or disorder selected fromleukemia, relapsed/refractory leukemia, acute lymphoblastic leukemia,Acute myelogenous leukemia, relapsed or refractory acute myeloidleukemia, atopic dermatitis, recurrent or metastatic carcinoma of theurothelium, advanced urothelial carcinoma, blood disorders,myelofibrosis, brain tumor, glioblastoma, glioma, meningioma, cancer,carcinomatous meningitis (neoplastic meningitis), choroidalneovascularization (CNV), subfoveal choroidal neovascularization,chronic lymphocytic leukemia, chronic myelogenous leukemia, refractorychronic myelogenous leukemia, colon cancer, colorectal cancer,degenerative nerve diseases, Neurodegenerative diseases, diabeticmacular edema, visual Impairment due to diabetic macular edema, diabeticretinopathy, dry eye syndrome (inflammation and corneal tissue damage ofdry Eye), endometrial cancer, eye diseases, ocular diseases, ocularneovascularization, eye cancer, Neurofibromatosis Type II, head and neckcancer, hematological malignancies, Kaposi's Sarcoma, HepatocellularCarcinoma, Lung cancer, macular degeneration, age related maculardegeneration, exudative age-related macular degeneration, neovascular(wet) age-related macular degeneration (AMD)), subfoveal NeovascularAge-Related macular degeneration, macular edema, macular edemaassociated with Branch Retinal Vein Occlusion, macular edema followingretinal vein occlusion, macular edema with Retinal Vein Occlusion (RVO),multiple myeloma, relapsed or refractory multiple myeloma, multiplesclerosis, myopia, pathological myopia, neuroendocrine tumor, carcinoidtumor, neuroendocrine tumor, non-Hodgkin's Lymphoma, Diffuse LargeB-Cell Lymphoma, Non-Small-Cell Lung cancer, Non-Squamous Non-Small-CellLung cancer, Non-small-cell-lung Adenocarcinoma, Squamous Non-Small-CellLung cancer, corneal graft rejection, osteoarthritis, recurrentsymptomatic malignant ascites, peripheral T-cell lymphoma, androgenIndependent Psoriasis, pulmonary Fibrosis, Idiopathic PulmonaryFibrosis, respiratory diseases, retinal detachment, retinal disorders,retinitis pigmentosa, retinal vein occlusion, branch retinal veinocclusion, central retinal vein occlusion, rheumatoid arthritis,sarcoma, alveolar soft part sarcoma, soft tissue sarcoma,scleroderma/systemic sclerosis, solid tumors, refractory germ celltumors, thyroid cancer, differentiated or medullar thyroid cancer, andWest Syndrome (Infantile Spasm).

In certain embodiments, the drug delivered to the suprachoroidal spaceusing the devices and methods disclosed herein is rapamycin (Sirolimus,Rapamune). In one embodiment, the devices (e.g., microneedle devices)and methods disclosed herein are used in conjunction with rapamycin totreat, prevent and/or ameliorate a wide range of diseases or disordersincluding, but not limited to: abdominal neoplasms, acquiredimmunodeficiency syndrome, acute coronary syndrome, acute lymphoblasticleukemia, acute myelocytic leukemia, acute non-lymphoblastic leukemia,adenocarcinoma, adenoma, adenomyoepithelioma, adnexal diseases,anaplastic astrocytoma, anaplastic large cell lymphoma, anaplasticplasmacytoma, anemia, angina pectoris, angioimmunoblasticlymphadenopathy with dysproteinemia, angiomyolipoma, arterial occlusivediseases, arteriosclerosis, astrocytoma, atherosclerosis, autoimmunediseases, B-cell lymphomas, blood coagulation disorders, blood proteindisorders, bone cancer, bone marrow diseases, brain diseases, brainneoplasms, breast beoplasms, bronchial neoplasms, carcinoid syndrome,carcinoid Tumor, carcinoma, squamous cell carcinoma, central nervoussystem diseases, central nervous system neoplasms, choroid diseases,choroid plexus neoplasms, choroidal neovascularization, choroiditis,chronic lymphocytic leukemia, chronic myeloid leukemia, chronicmyelomonocytic leukemia, chronic myeloproliferative disorders, chronicneutrophilic leukemia, clear cell renal cell carcinoma, colonicdiseases, colonic neoplasms, colorectal neoplasms, coronary arterydisease, coronary disease, coronary Occlusion, coronary restenosis,coronary stenosis, coronary thrombosis, cutaneous T-cell lymphoma,diabetes mellitus, digestive system neoplasms, dry eye syndromes, eardiseases, edema, endocrine gland neoplasms, endocrine system diseases,endometrial neoplasms, Endometrial stromal tumors, Ewing's sarcoma,exanthema, eye neoplasms, fibrosis, follicular lymphoma,gastrointestinal diseases, gastrointestinal neoplasms, genitalneoplasms, glioblastoma, glioma, gliosarcoma, graft vs host disease,hematologic diseases, hematologic neoplasms, hemorrhagic disorders,hemostatic disorders, Hodgkin disease, Hodgkin lymphoma, homologouswasting disease, immunoblastic lymphadenopathy, immunologic deficiencysyndromes, immunoproliferative disorders, infarction, inflammation,intestinal diseases, intestinal neoplasms, ischemia, kidney cancer,kidney diseases, kidney neoplasms, leukemia, B-Cell, leukemia, lymphoid,liver cancer, liver diseases, lung diseases, lymphatic diseases,lymphoblastic lymphoma, lymphoma, macular degeneration, macular edema,melanoma, mouth neoplasms, multiple myeloma, myelodysplastic syndromes,myelofibrosis, myeloproliferative disorders, neuroectodermal tumors,neuroendocrine tumors, neuroepithelioma, neurofibroma, renal cancer,respiratory tract diseases, retinal degeneration, retinal diseases,retinal neoplasms, retinoblastoma, rhabdomyosarcoma, thoracic neoplasms,uveitis, vascular diseases, Waldenstrom Macroglobulinemia, and wetmacular degeneration. In addition, delivery of rapamycin using themicroneedle devices and methods disclosed herein may be combined withone or more agents listed herein or with other agents known in the art.

In one embodiment, the drug delivered to ocular tissue, for example thesclera or suprachoroidal space, using the microneedle devices andmethods disclosed herein reduces, inhibits, prevents and/or amelioratesinflammation. Examples of drugs that reduce, inhibit, prevent and/orameliorate inflammation include (but are not limited to): 19AV Agonists,19GJ agonists, 2MD Analogs, 4SC101, 4SC102, 57-57, 5-HT2 ReceptorAntagonist, 64G12, A804598, A967079, AAD2004, AB1010, AB224050,abatacept, Abegrin, Abevac, AbGn134, AbGn168, Abki, ABN912, ABR215062,ABR224050, Abrammune, Abreva, ABS15, ABS4, ABS6, ABT122, ABT325, ABT494,ABT874, ABT963, ABXIL8, ABXRB2, AC430, Accenetra, Acdeam, ACE772,Acebid, Acebloc, aceclofenac, acetaminophen, chlorzoxazone,serrapeptase, tizanidine hydrochloride, betadex, Aceclogesic Plus,Aceclon, Acecloren, Aceclorism, acecrona, Aceffein, acemetacin, Acenac,Acenterine, Acetal-SP, ibuprofen, Acetyl-G, acetylsalicylate dl-lysine,acetylsalicylic acid, Acicot, Acifine, Acik, Aclocen, Acloflam-P,Aclomore, Aclon, A-CQ, ACS15, actarit, Actemra, Acthelea liofilizado,Actifast, Actimab-B, Actiquim, Actirin, Actis PLUS, activated leukocytecell adhesion molecule antibody, Acular X, AD452, adalimumab, ADAMTS5Inhibitor, ADC1001, Adco-Diclofenac, Adco-Indomethacin, Adco-Meloxicam,Adco-Naproxen, Adco-Piroxicam, Adcort, Adco-Sulindac, adenosinetriphosphate disodium, AdenosineA2a Receptor Agonist, Adimod, Adinos,Adioct, Adiodol, Adipoplus, adipose derived stem and/or regenerativecells, Adizen, Adpep, Advacan, Advagraf, Advel, Adwiflam, AEB071,Aental, Afenac, Affen Plus, Afiancen, Afinitor, Aflamin, Aflazacort,Aflogen, Afloxan, AFM15, AFM16, AFM17, AFM23, Afpred-Dexa, AFX200,AG011, Agafen, aganirsen, AGI1096, Agidex, AGS010, Agudol, A-Hydrocort,AIK1, AIN457, Airtal, AIT110, AJM300, ajulemic acid, AK106, AL-24-2A1,AL4-1A1, Ala Cort, Alanz, Albumin immune-globulin, alclometasonedipropionate, ALD518, aldesleukin, Aldoderma, alefacept, alemtuzumab,Alequel, Alergolon, Alergosone, Aletraxon, Alfenac, Algason, Algin vekcoat, Algioflex, Algirex, Algivin Plus, alicaforsen sodium, Alin,Alinia, Aliviodol, Aliviosin, alkaline phosphatase, ALKS6931, allantoin,Allbupen, Allmol, Allochrysine, allogeneic endothelial cells, allogeneicmesenchymal precursor cells, allogeneic mesenchymal stem cells,alminoprofen, alpha 1 antitrypsin, Alpha 7 nicotinic agonists, alphaamylase, alpha chymotrypsin, alpha fetoprotein, alpha linolenic acid,Alpha-1-antitrypsin, Alpha2Beta1 Integrin Inhibitors, Alphacort,Alphafen, alpha-hexidine, alpha-trypsin, Alphintern, Alpinamed mobilityomega 3, Alpoxen, AL-Rev1, Alterase, ALX0061, ALX0761, ALXN1007,ALXN1102, AM3840, AM3876, AMAB, AMAP102, Amason, Ambene, AmbezimG,amcinonide, AME133v, Amecin, Ameloteks, A-Methapred, Amevive, AMG108,AMG139, AMG162, AMG181, AMG191, AMG220, AMG623, AMG674, AMG714, AMG719,AMG729, AMG827, Amidol, amifampridine phosphate, Amifenac, Amimethacin,amiprilose hydrochloride, Amiprofen, Ammophos, Amoflam, AMP110, Ampikyy,Ampion, ampiroxicam, amtolmetin guacil, AMX256, AN6415, ANA004, ANA506,Anabu, Anacen, Anaflam, Anaflex ACI, Anaida, anakinra, Analgen Artritis,Anapan, Anaprox, Anavan, Anax, Anco, andrographis, Aneol, Anergix,Anervax.RA, Anflene, ANG797, Anilixin, Anmerushin, Annexin 1 peptides,annexin A5, Anodyne, Ansaid, Anspirin, Antarene, Anti BST2 antibody,Anti C5a MAb, Anti ILT7 antibody, Anti VLA1 antibody, Anti-alpha1 1antibody, Anti-CD4 802-2, Anti-CD86 Monoclonal Antibody, Anti-chemokine,Anti-DC-SIGN, Anti-HMGB-1 MAb, Anti-IL-18 Mab, Anti-IL-1R MAb,Anti-IL-1R MAb, Anti-IL23 BRISTOL, Anti-inflammatory Peptides,Anti-interleukin 1Beta antibody, Anti-LIGHT antibody, Anti-LIGHTantibody, Anti-MIF Antibody, Anti-MIF Antibody, Anti-miR181a,antioxidant inflammation modulators, Antiphlamine, AntiRAGE MAb,antithrombin III, Anti-TIRC-7MAb, Anusol-HC, Anyfen, AP105, AP1089,AP1189, AP401, AP501, apazone, APD334, Apentac, APG103, Apidone,apilimod mesylate, Apitac, Apitoxin, Apizel, APN Inhibitor,apo-Azathioprine, Apo-Dexamethasone, ApoE mimetics, ApoFasL,apo-Indomethacin, apo-mefenamic, apo-methotrexate, apo-nabumetone,Apo-Napro-NA, apo-Naproxen, aponidin, apo-Phenylbutazone, apo-Piroxicam,apo-Sulin, Apo-Tenoxicam, apo-Tiaprofenic, Apranax, apremilast,apricoxib, Aprofen, Aprose, Aproxen, APX001 antibody, APX007 antibody,APY0201, AqvoDex, AQX108, AQX1125, AQX131135, AQX140, AQX150, AQX200,AQX356, AQXMN100, AQXMN106, ARA290, Arava, Arcalyst, Arcoxia, Arechin,Arflur, ARG098, ARG301, arginine aescin, arginine deiminase (pegylated),ARGX109 antibody, ARGX110, Arheuma, Aristocort, Aristospan, Ark-AP,ARN4026, Arofen, Aroff EZ, Arolef, Arotal, Arpibru, Arpimune, ArpuShuangxin, ARQ101, Arrestin SP, Arrox, ARRY162, ARRY371797, ARRY614,ARRY872, ART621, Artamin, Arthfree, Artho Tech, Arthrexin, Arthrispray,Arthrotec, Arthrovas, Artifit, Artigo, Artin, Artinor, Artisid,Artoflex, Artren Hipergel, Artridol, Artrilase, Artrocaptin, Artrodiet,Artrofen, Artropan, Artrosil, Artrosilene, Artrotin, Artrox, Artyflam,Arzerra, AS604850, AS605858, Asacol, ASA-Grindeks, Asazipam, Aseclo,ASF1096, ASF1096, ASK8007, ASKP1240, ASLAN003, Asmo ID, Asonep, ASP015K,ASP2408, ASP2409, Aspagin, Aspeol, Aspicam, Aspirimex, aspirin, AST120,astaxanthin, AstroCort, Aszes, AT002antibody, AT007, AT008 antibody,AT008 antibody, AT010, AT1001, atacicept, Ataspin, Atepadene, Atgam,ATG-Fresenius, Athrofen, ATI003, atiprimod, ATL1222, ATN103, ATN192,ATR107, Atri, Atrmin, Atrosab antibody, ATX3105, AU801, auranofin,Aurobin, Auropan, Aurothio, aurotioprol, autologous adipose derivedregenerative cells, Autonec, Avandia, AVE9897, AVE9940, Avelox, Avent,AVI3378, Avloquin, AVP13546, AVP13748, AVP28225, AVX002, AxcelDiclofenac, Axcel Papain, Axen, AZ17, AZ175, Azacortid, AZA-DR,Azafrine, Azamun, Azanin, Azap, Azapin, Azapren, Azaprin, Azaram,Azasan, azathioprine, AZD0275, AZD0902, AZD2315, AZD5672, AZD6703,AZD7140, AZD8309, AZD8566, AZD9056, Azet, Azintrel, azithromycin, Az-od,Azofit, Azolid, Azoran, Azulene, Azulfidine, Azulfin, B1 antagonists,Baclonet, BAF312, BAFF Inhibitor, Bages, Baily S.P., Baleston,Balsolone, baminercept alfa, bardoxolone methyl, baricitinib, Barotase,Basecam, basiliximab, Baxmune, Baxo, BAY869766, BB2827, BCX34, BCX4208,Becfine, Beclate-C, Beclate-N, Beclolab Q, beclomethasone dipropionate,Beclorhin, Becmet-CG, Begita, Begti, belatacept, belimumab, Belosalic,Bemetson, Ben, Benevat, Benexam, Benflogin, Benisan, Benlysta, Benlysta,benorilate, Benoson, benoxaprofen, Bentol, benzydamine hydrochloride,Benzymin, Beofenac, Berafen, Berinert, Berlofen, Bertanel, Bestamine,Bestofen, Beta Nicip, Betacort, Betacorten G, Betafoam, beta-glucan,Betalar, Beta-M, Betamed, Betamesol, betamethasone, betamethasonedipropionate, betamethasone sodium, betamethasone sodium phosphate,betamethasone valerate, Betane, Betanex, Betapanthen, Betapar, Betapred,Betason, Betasonate, Betasone, Betatrinta, Betaval, Betazon, Betazone,Betesil, Betnecort, Betnesol, Betnovate, Bextra, BFPC13, BFPC18, BFPC21,BFPT6864, BG12, BG9924, BI695500, BI695501, BIA12, Big-Joint-D, BIIB023antibody, Bi-ksikam, Bingo, BioBee, Bio-Cartilage, Bio-C-Sinkki,Biodexone, Biofenac, Bioreucam, Biosone, Biosporin, BIRB796, Bitnoval,Bitvio, Bivigam, BKT140, BKTP46, BL2030, BL3030, BL4020, BL6040, BL7060,BLI1300, blisibimod, Blokium B12, Blokium Gesic, Blokium, BMS066,BMS345541, BMS470539, BMS561392, BMS566419, BMS582949, BMS587101,BMS817399, BMS936557, BMS945429, BMS-A, BN006, BN007, BNP166, Bonacort,Bonas, bone marrow stromal cell antigen 2 antibody, Bonflex, Bonifen,Boomiq, Borbit, Bosong, BR02001, BR3-FC, Bradykinin B1 ReceptorAntagonist, Bredinin, Brexecam, Brexin, Brexodin, briakinumab, Brimani,briobacept, Bristaflam, Britten, Broben, brodalumab, Broen-C,bromelains, Bromelin, Bronax, Bropain, Brosiral, Bruace, Brufadol,Brufen, Brugel, Brukil, Brusil, BT061, BTI9, BTK kinase inhibitors,BTT1023 antibody, BTT1507, bucillamine, Bucillate, Buco Reigis,bucolome, Budenofalk, budesonide, Budex, Bufect, Bufencon, BukwangKetoprofen, Bunide, Bunofen, Busilvex, busulfan, Busulfex, Busulipo,Butartrol, Butarut B12, Butasona, Butazolidin, Butesone, Butidiona,BVX10, BXL628, BYM338, B-Zone, C1 esterase inhibitor, C243, c4462,c5997, C5aQb, c7198, c9101, C9709, c9787, CAB101, cadherin 11 antibody,caerulomycin A, CAL263, Calcort, Calmatel, CAM3001, Camelid Antibodies,Camlox, Camola, Campath, Camrox, Camtenam, canakinumab, candida albicansantigen, Candin, cannabidiol, CAP1.1, CAP1.2, CAP2.1, CAP2.2, CAP3.1,CAP3.2, Careram, Carimune, Cariodent, Cartifix, CartiJoint, Cartilago,Cartisafe-DN, Cartishine, Cartivit, Cartril-S, Carudol, CaspaCIDe,CaspaCIDe, Casyn, CAT1004, CAT1902, CAT2200, Cataflam, Cathepsin Sinhibitor, Catlep, CB0114, CB2 agonist, CC0478765, CC10004, CC10015,CC1088, CC11050, CC13097, CC15965, CC16057, CC220, CC292, CC401, CC5048,CC509, CC7085, CC930, CCR1 Antagonist, CCR6 Inhibitor, CCR7 Antagonist,CCRL2 antagonist, CCX025, CCX354, CCX634, CD Diclofenac, CD102, CD103Antibody, CD103 Antibody, CD137 antibody, CD16 antibody, CD18 antibody,CD19 antibody, CD1d Antibody, CD20 antibody, CD200Fc, CD209 antibody,CD24, CD3 antibody, CD30 antibody, CD32A antibody, CD32B antibody, CD4antibody, CD40 ligand, CD44 antibody, CD64 antibody, CDC839, CDC998,CDIM4, CDIM9, CDK9-Inhibitor, CDP146, CDP323, CDP484, CDP6038,CDP870,CDX1135, CDX301, CE224535, Ceanel, Cebedex, Cebutid, Ceclonac,Ceex, CEL2000, Celact, Celbexx, Celcox, Celebiox, Celebrex, Celebrin,Celecox, celecoxib, Celedol, Celestone, Celevex, Celex, CELG4, Celladhesion molecule antagonists, CellCept, Cellmune, Celosti, Celoxib,Celprot, Celudex, cenicriviroc mesylate, cenplacel-1, CEP11004,CEP37247, CEP37248, Cephyr, Ceprofen, Certican, certolizumab pegol,Cetofenid, Cetoprofeno, cetylpyridinium chloride, CF101, CF402, CF502,CG57008, CGEN15001, CGEN15021, CGEN15051, CGEN15091, CGEN25017,CGEN25068, CGEN40, CGEN54, CGEN768, CGEN855, CGI1746, CGI560, CGI676,Cgtx-Peptides, CH1504, CH4051, CH4446, chaperonin 10, chemokine C-Cmotif ligand 2, chemokine C-C motif ligand 2 antibody, chemokine C-Cmotif ligand 5 antibody, chemokine C-C motif receptor 2 antibody,chemokine C-C motif receptor 4 antibody, chemokine C-X-C motif ligand 10antibody, chemokine C-X-C motif ligand 12 aptamer, Chemotaxis Inhibitor,Chillmetacin, chitinase 3-like 1, Chlocodemin, Chloquin, chlorhexidinegluconate, chloroquine phosphate, choline magnesium trisalicylate,chondroitin sulfate, Chondroscart, CHR3620, CHR4432, CHR5154, Chrysalin,Chuanxinlian, Chymapra, Chymotase, chymotrypsin, Chytmutrip, CI202,CI302, Cicloderm-C, Ciclopren, Cicporal, Cilamin, Cimzia, cinchophen,cinmetacin, cinnoxicam, Cinoderm, Cinolone-S, Cinryze, Cipcorlin,cipemastat, Cipol-N, Cipridanol, Cipzen, Citax F, Citogan, Citoken T,Civamide, CJ042794, CJ14877, c-Kit monoclonal antibody, cladribine,Clafen, Clanza, Claversal, clazakizumab, Clearoid, Clease, Clevegen,Clevian, Clidol, Clindac, Clinoril, Cliptol, Clobenate, Clobequad,clobetasol butyrate, clobetasol propionate, Clodol, clofarabine, Clofen,Clofenal LP, Clolar, Clonac, Clongamma, clonixin lysine, Clotasoce,Clovacort, Clovana, Cloxin, CLT001, CLT008, C-MAF Inhibitor, CMPX1023,Cnac, CNDO201, CNI1493, CNTO136, CNTO148, CNTO1959, Cobefen,CoBenCoDerm, Cobix, Cofenac, Cofenac, COG241, COL179, colchicine,Colchicum Dispert, Colchimax, Colcibra, Coledes A, Colesol, Colifoam,Colirest, collagen, type V, Comcort, complement component (3b/4b)receptor 1, Complement Component Cls Inhibitors, complement componentC3, complement factor 5 a receptor antibody, complement factor 5areceptor antibody, complement factor D antibody, Condrosulf, Condrotec,Condrothin, conestat alfa, connective tissue growth factor antibody,Coolpan, Copaxone, Copiron, Cordefla, Corhydron, Cort S, Cortan,Cortate, Cort-Dome, Cortecetine, Cortef, Corteroid, Corticap, Corticas,Cortic-DS, corticotropin, Cortiderm, Cortidex, Cortiflam, Cortinet M,Cortinil, Cortipyren B, Cortiran, Cortis, Cortisolu, cortisone acetate,Cortival, Cortone acetate, Cortopin, Cortoral, Cortril, Cortypiren,Cosamine, Cosone, cosyntropin, COT Kinase Inhibitor, Cotilam, Cotrisone,Cotson, Covox, Cox B, COX-2/5-LO Inhibitors, Coxeton, Coxflam, Coxicam,Coxitor, Coxtral, Coxypar, CP195543, CP412245, CP424174, CP461,CP629933, CP690550, CP751871, CPSI2364, C-quin, CR039, CR074, CR106,CRA102, CRAC channel inhibitor, CRACM Ion Channel Inhibitor, Cratisone,CRB15, CRC4273, CRC4342, C-reactive protein 2-methoxyethylphosphorothioate oligonucleotide, CreaVax-RA, CRH modulators,critic-aid, Crocam, Crohnsvax, Cromoglycic acid, cromolyn sodium,Cronocorteroid, Cronodicasone, CRTX803, CRx119, CRx139, CRx150, CS502,CS670, CS706, CSF1R Kinase Inhibitors, CSL324, CSL718, CSL742, CT112,CT1501R, CT200, CT2008, CT2009, CT3, CT335, CT340, CT5357, CT637, CTP05,CTP10, CT-P13, CTP17, Cuprenil, Cuprimine, Cuprindo, Cupripen, Curaquin,Cutfen, CWF0808, CWP271, CX1020, CX1030, CX1040, CX5011, Cx611, Cx621,Cx911, CXC chemokine receptor 4 antibody, CXCL13 antibodies, CXCR3antagonists, CXCR4 antagonist, Cyathus 1104 B, Cyclo-2, Cyclocort,cyclooxygenase-2 inhibitor, cyclophosphamide, Cyclorine, Cyclosporin AProdrug, Cyclosporin analogue A, cyclosporine, Cyrevia, Cyrin CLARIS,CYT007TNFQb, CYT013IL1bQb, CYT015IL17Qb, CYT020TNFQb, CYT107, CYT387,CYT99007, cytokine inhibitors, Cytopan, Cytoreg, CZC24832, D1927,D9421C, daclizumab, danazol, Danilase, Dantes, Danzen, dapsone, Dase-D,Daypro, Daypro Alta, Dayrun, Dazen, DB295, DBTP2, D-Cort, DD1, DD3,DE096, DE098, Debio0406, Debio0512, Debio0615, Debio0618, Debio1036,Decaderm, Decadrale, Decadron, Decadronal, Decalon, Decan, Decason,Decdan, Decilone, Declophen, Decopen, Decorex, Decorten, Dedema, Dedron,Deexa, Defcort, De-flam, Deflamat, Deflan, Deflanil, Deflaren, Deflaz,deflazacort, Defnac, Defnalone, Defnil, Defosalic, Defsure, Defza,Dehydrocortison, Dekort, Delagil, delcasertib, delmitide, Delphicort,Deltacorsolone, Deltacortril, Deltafluorene, Deltasolone, Deltasone,Deltastab, Deltonin, Demarin, Demisone, Denebola, denileukin diftitox,denosumab, Denzo, Depocortin, Depo-medrol, Depomethotrexate, Depopred,Deposet, Depyrin, Derinase, Dermol, Dermolar, Dermonate, Dermosone,Dersone, Desketo, desonide, desoxycorticosterone acetate, Deswon, Dexa,Dexabene, Dexacip, Dexacort, Dexacortisone, Dexacotisil, Dexadic,Dexadrin, Dexadron, Dexafar, Dexahil, Dexalab, Dexalaf, Dexalet,Dexalgen, Dexallion, Dexalocal, Dexalone, Dexa-M, Dexamecortin, Dexamed,Dexamedis, Dexameral, Dexameta, Dexamethasone, dexamethasone acetate,dexamethasone palmitate, dexamethasone phosphate, dexamethasone sodiummetasulfobenzoate, dexamethasone sodium phosphate, Dexamine,Dexapanthen, Dexa-S, Dexason, Dexatab, Dexatopic, Dexaval, Dexaven,Dexazolidin, Dexazona, Dexazone, Dexcor, Dexibu, dexibuprofen, Dexico,Dexifen, Deximune, dexketoprofen, dexketoprofen trometamol, Dexmark,Dexomet, Dexon I, Dexonalin, Dexonex, Dexony, Dexoptifen, Dexpin,Dextan-Plus, dextran sulfate, Dezacor, Dfz, diacerein, Diannexin,Diastone, Dicarol, Dicasone, Dicknol, Diclo, Diclobon, Diclobonse,Diclobonzox, Diclofast, Diclofen, diclofenac, diclofenacbeta-dimethylaminoethanol, diclofenac deanol, diclofenac diethylamine,diclofenac epolamine, diclofenac potassium, diclofenac resinate,diclofenac sodium, Diclogen AGIO, Diclogen Plus, Diclokim, Diclomed,Diclo-NA, Diclonac, Dicloramin, Dicloran, Dicloreum, Diclorism,Diclotec, Diclovit, Diclowal, Diclozem, Dico P, Dicofen, Dicoliv,Dicorsone, Dicron, Dicser, Difena, Diffutab, diflunisal, dilmapimod,Dilora, dimethyl sulfone, Dinac, D-Indomethacin, Dioxaflex Protect,Dipagesic, Dipenopen, Dipexin, Dipro AS, Diprobeta, Diprobetasone,Diproklenat, Dipromet, Dipronova, Diprosone, Diprovate, Diproxen,Disarmin, Diser, Disopain, Dispain, Dispercam, Distamine, Dizox, DLT303,DLT404, DM199, DM99, DMI9523, dnaJP1, DNX02070, DNX04042, DNX2000,DNX4000, docosanol, Docz-6, Dolamide, Dolaren, Dolchis, Dolex, Dolflam,Dolfre, Dolgit, Dolmax, Dolmina, Dolo Ketazon, Dolobest, Dolobid, Doloc,Dolocam, Dolocartigen, Dolofit, Dolokind, Dolomed, Dolonac, Dolonex,Dolotren, Dolozen, Dolquine, Dom0100, Dom0400, Dom0800, Domet, Dometon,Dominadol, Dongipap, Donica, Dontisanin, doramapimod, Dorixina Relax,Dormelox, Dorzine Plus, Doxatar, Doxtran, DP NEC, DP4577, DP50, DP6221,D-Penamine, DPIV/APN Inhibitors, DR1 Inhibitors, DR4 Inhibitors, DRA161,DRA162, Drenex, DRF4848, DRL15725, Drossadin, DSP, Duexis, Duo-Decadron,Duoflex, Duonase, DV1079, DV1179, DWJ425, DWP422, Dymol, DYN15, Dynapar,Dysmen, E5090, E6070, Easy Dayz, Ebetrexat, EBI007, EC0286, EC0565,EC0746, Ecax, echinacea purpurea extract, EC-Naprosyn, Econac, Ecosprin300, Ecosprin 300, Ecridoxan, eculizumab, Edecam, efalizumab,Efcortesol, Effigel, Eflagen, Efridol, EGFR Antibody, EGS21, eIF5A1siRNA, Ekarzin, elafin, Eldoflam, Elidel, Eliflam, Elisone, Elmes,Elmetacin, ELND001, ELND004, elocalcitol, Elocom, elsibucol, Emanzen,Emcort, Emifen, Emifenac, emorfazone, Empynase, emricasan, Emtor,Enable, Enbrel, Enceid, EncorStat, Encortolon, Encorton, Endase,Endogesic, Endoxan, Enkorten, Ensera, Entocort, Enzylan, Epanova,Eparang, Epatec, Epicotil, epidermal growth factor receptor 2 antibody,epidermal growth factor receptor antibody, Epidixone, Epidron, Epiklin,EPPA1, epratuzumab, EquiO, Erac, Erazon, ERB041, ERB196, Erdon, EryDex,escherichia coli enterotoxin B subunit, Escin, E-Selectin Antagonists,Esfenac, ESN603, esonarimod, Esprofen, estetrol, Estopein, EstrogenReceptor beta agonist, etanercept, etaracizumab, ETC001, ethanolpropolis extract, ETI511, etiprednol dicloacetate, Etodin, Etodine,Etodol, etodolac, Etody, etofenamate, Etol Fort, Etolac, Etopin,etoricoxib, Etorix, Etosafe, Etova, Etozox, Etura, Eucob, Eufans,eukaryotic translation initiation factor 5A oligonucleotide, Eunac,Eurocox, Eurogesic, everolimus, Evinopon, EVT401, Exaflam, EXEL9953,Exicort, Expen, Extra Feverlet, Extrapan, Extrauma, Exudase, F16, F991,Falcam, Falcol, Falzy, Farbovil, Farcomethacin, Farnerate, Farnezone,Farnezone, Farotrin, fas antibody, Fastflam, FasTRACK, Fastum,Fauldmetro, FcgammaRIA antibody, FE301, Febrofen, Febrofid, felbinac,Feldene, Feldex, Feloran, Felxicam, Fenac, Fenacop, Fenadol, Fenaflan,Fenamic, Fenaren, Fenaton, Fenbid, fenbufen, Fengshi Gutong, Fenicort,Fenopine, fenoprofen calcium, Fenopron, Fenris, Fensupp, Fenxicam,fepradinol, Ferovisc, Feverlet, fezakinumab, FG3019, FHT401, FHTCT4,FID114657, figitumumab, Filexi, filgrastim, Fillase, Final, Findoxin,fingolimod hydrochloride, firategrast, Firdapse, Fisiodar, Fivasa,FK778, Flacoxto, Fladalgin, Flagon, Flamar, Flamcid, Flamfort, Flamide,Flaminase, Flamirex Gesic, Flanid, Flanzen, Flaren, Flaren, Flash Act,Flavonoid Anti-inflammatory Molecule, Flebogamma DIF, Flenac, Flex,Flexafen 400, Flexi, Flexidol, Flexium, Flexon, Flexono, Flogene,Flogiatrin B12, Flogomin, Flogoral, Flogosan, Flogoter, Flo-Pred,Flosteron, Flotrip Forte, Flt3 inhibitors, fluasterone, Flucam,Flucinar, fludrocortisone acetate, flufenamate aluminum, flumethasone,Flumidon, flunixin, fluocinolone, fluocinolone acetonide, fluocinonide,fluocortolone, Fluonid, fluorometholone, Flur, flurbiprofen, Fluribec,Flurometholone, Flutal, fluticasone, fluticasone propionate, Flutizone,Fluzone, FM101 antibody, fms-related tyrosine kinase 1 antibody,Folitrax, fontolizumab, formic acid, Fortecortin, Fospeg, fostamatinibdisodium, FP1069, FP13XX, FPA008, FPA031, FPT025, FR104, FR167653,Framebin, Frime, Froben, Frolix, FROUNT Inhibitors, Fubifen PAP, Fucoleibuprofen, Fulamotol, Fulpen, Fungifin, Furotalgin, fusidate sodium,FX002, FX141L, FX201, FX300, FX87L, Galectin modulators, galliummaltolate, Gamimune N, Gammagard, Gamma-I.V., GammaQuin, Gamma-Venin,Gamunex, Garzen, Gaspirin, Gattex, GBR500, GBR500 antibody, GBT009,G-CSF, GED0301, GED0414, Gefenec, Gelofen, Genepril, Gengraf, Genimune,Geniquin, Genotropin, Genz29155, Gerbin, Gerbin, gevokizumab,GF01564600, Gilenia, Gilenya, givinostat, GL0050, GL2045, glatirameracetate, Globulin, Glortho Forte, Glovalox, Glovenin-I, GLPG0259,GLPG0555, GLPG0634, GLPG0778, GLPG0974, Gluco, Glucocerin, glucosamine,glucosamine hydrochloride, glucosamine sulfate, Glucotin, Gludex,Glutilage, GLY079, GLY145, Glycanic, Glycefort up, Glygesic, Glysopep,GMCSF Antibody, GMI1010, GMI1011, GMI1043, GMR321, GN4001, Goanna Salve,Goflex, gold sodium thiomalate, golimumab, GP2013, GPCR modulator, GPR15Antagonist, GPR183 antagonist, GPR32 antagonist, GPR83 antagonist,G-protein Coupled Receptor Antagonists, Graceptor, Graftac, granulocytecolony-stimulating factor antibody, granulocyte-macrophagecolony-stimulating factor antibody, Gravx, GRC4039, Grelyse, GS101,GS9973, GSC100, GSK1605786, GSK1827771, GSK2136525, GSK2941266,GSK315234, GSK681323, GT146, GT442, Gucixiaotong, Gufisera, Gupisone,gusperimus hydrochloride, GW274150, GW3333, GW406381, GW856553, GWB78,GXP04, Gynestrel, Haloart, halopredone acetate, Haloxin, HANALL, HanallSoludacortin, Havisco, Hawon Bucillamin, HB802, HC31496, HCQ 200, HD104,HD203, HD205, HDAC inhibitor, HE2500, HE3177, HE3413, Hecoria,Hectomitacin, Hefasolon, Helen, Helenil, HemaMax, Hematom, hematopoieticstem cells, Hematrol, Hemner, Hemril, heparinoid, Heptax, HER2 Antibody,Herponil, hESC Derived Dendritic Cells, hESC Derived Hematopoietic stemcells, Hespercorbin, Hexacorton, Hexadrol, hexetidine, Hexoderm,Hexoderm Salic, HF0220, HF1020, HFT-401, hG-CSFR ED Fc, Hiberna, highmobility group box 1 antibody, Hiloneed, Hinocam, hirudin, Hirudoid,Hison, Histamine H4 Receptor Antagonist, Hitenercept, Hizentra, HL036,HL161, HMPL001, HMPL004, HMPL004, HMPL011, HMPL342, HMPL692, honey beevenom, Hongqiang, Hotemin, HPH116, HTI101, HuCAL Antibody, Human adiposemesenchymal stem cells, anti-MHC class II monoclonal antibody, HumanImmunoglobulin, Human Placenta Tissue Hydrolysate, HuMaxCD4, HuMax-TAC,Humetone, Humicade, Humira, Huons Betamethasone sodium phosphate, Huonsdexamethasone sodium phosphate, Huons Piroxicam, Huons Talniflumate,Hurofen, Huruma, Huvap, HuZAF, HX02, Hyalogel, hyaluronate sodium,hyaluronic acid, hyaluronidase, Hyaron, Hycocin, Hycort, Hy-Cortisone,hydrocortisone, hydrocortisone acetate, hydrocortisone butyrate,hydrocortisone hemisuccinate, hydrocortisone sodium phosphate,hydrocortisone sodium succinate, Hydrocortistab, Hydrocortone, Hydrolin,Hydroquine, Hydro-Rx, Hydrosone HIKMA, hydroxychloroquine,hydroxychloroquine sulfate, Hylase Dessau, HyMEX, Hypen, HyQ, Hysonate,HZN602, I.M.75, IAP Inhibitors, Ibalgin, Ibalgin, Ibex, ibrutinib,IBsolvMIR, Ibu, Ibucon, Ibudolor, Ibufen, Ibuflam, Ibuflex, Ibugesic,Ibu-Hepa, Ibukim, Ibumal, Ibunal, Ibupental, Ibupril, Ibuprof,ibuprofen, Ibuscent, Ibusoft, Ibusuki Penjeong, Ibususpen, Ibutard,Ibutop, Ibutop, Ibutrex, IC487892, ichthammol, ICRAC Blocker, IDEC131,IDECCE9.1, Ides, Idicin, Idizone, IDN6556, Idomethine, IDR1, Idyl SR,Ifen, iguratimod, IK6002, IKK-beta inhibitor, IL17 Antagonist, IL-17Inhibitor, IL-17RC, IL18, IL1Hy1, IL1R1, IL-23 Adnectin, IL23 Inhibitor,IL23 Receptor Antagonist, IL-31 mAb, IL-6 Inhibitor, IL6Qb, Ilacox,Ilaris, ilodecakin, ILV094, ILV095, Imaxetil, IMD0560, IMD2560, ImeselPlus, Iminoral, Immodin, IMMU103, IMMU106, Immucept, Immufine, ImmunexSyrup, immunoglobulin, immunoglobulin G, Immunoprin, ImmunoRel, Immurin,IMO8400, IMP731 antibody, Implanta, Imunocell, Imuran, Imurek, Imusafe,Imusporin, Imutrex, IN0701, Inal, INCB039110, INCB18424, INCB28050,INCB3284, INCB3344, Indexon, Indic, Indo, Indo-A, Indobid, Indo-Bros,Indocaf, Indocarsil, Indocid, Indocin, Indomehotpas, Indomen, Indomet,Indometacin, indomethacin, Indomethasone, Indometin, Indomin, Indopal,Indoron, Indotroxin, INDUS830, INDUS83030, Infladase, Inflamac,Inflammasome inhibitor, Inflavis, Inflaxen, Inflectra, infliximab,Ingalipt, Inicox dp, Inmecin, Inmunoartro, Innamit, InnoD06006, INO7997,Inocin, Inoten, Inovan, Inpra, Inside Pap, Insider-P, Instacyl,Instracool, Intafenac, Intaflam, Inteban, Inteban Spansule, integrin,alpha 1 antibody, integrin, alpha 2 antibody, Intenurse, interferonalfa, interferon beta-1a, interferon gamma, interferon gamma antibody,Interking, interleukin 1 Hy1, interleukin 1 antibody, interleukin 1receptor antibody, interleukin 1, beta antibody, interleukin 10,interleukin 10 antibody, interleukin 12, interleukin 12 antibody,interleukin 13 antibody, interleukin 15 antibody, interleukin 17antibody, interleukin 17 receptor C, interleukin 18, interleukin 18binding protein, interleukin 18 antibody, interleukin 2 receptor, alphaantibody, interleukin 20 antibody, Interleukin 21 mAb, interleukin 23aptamer, interleukin 31 antibody, interleukin 34, Interleukin 6Inhibitor, interleukin 6 antibody, interleukin 6 receptor antibody,interleukin 7, interleukin 7 receptor antibody, interleukin 8,interleukin 8 antibody, interleukin-18 antibody, Intidrol, Intradex,Intragam P, Intragesic, Intraglobin F, Intratect, Inzel, Iomab B,IOR-T3, IP751, IPH2201, IPH2301, IPH24, IPH33, IP1145, Ipocort,IPP201007, I-Profen, Iprox, Ipson, Iputon, IRAK4 Inhibitor, Iremod,Irtonpyson, IRX3, IRX5183, ISA247, ISIS104838, ISIS2302, ISISCRPRx,Ismafron, IsoQC inhibitor, Isox, ITF2357, Iveegam EN, Ivepred, IVIG-SN,IW001 Izilox, J607Y, J775Y, JAK Inhibitor, JAK3 inhibitor, JAK3 kinaseinhibitor, JI3292, JI4135, Jinan Lida, JNJ10329670, JNJ18003414,JNJ26528398, JNJ27390467, JNJ28838017, JNJ31001958, JNJ38518168,JNJ39758979, JNJ40346527, JNJ7777120, JNT-Plus, Joflam, JointGlucosamin, Jointec, Jointstem, Joinup, JPE1375, JSM10292, JSM7717,JSM8757, JTE051, JTE052, JTE522, JTE607, Jusgo, K412, K832, Kaflam,KAHR101, KAHR102, KAI9803, Kalymin, Kam Predsol, Kameton, KANAb071,Kappaproct, KAR2581, KAR3000, KAR3166, KAR4000, KAR4139, KAR4141, KB002,KB003, KD7332, KE298, keliximab, Kemanat, Kemrox, Kenacort, Kenalog,Kenaxir, Kenketsu Venoglobulin-IH, Keplat, Ketalgipan, Keto Pine, Keto,Ketobos, Ketofan, Ketofen, Ketolgan, Ketonal, Ketoplus Kata Plasma,ketoprofen, Ketores, Ketorin, ketorolac, ketorolac tromethamine,Ketoselect, Ketotop, Ketovail, Ketricin, Ketroc, Ketum, Keyi, Keyven,KF24345, K-Fenac, K-Fenak, K-Gesic, Kifadene, Kilcort, Kildrol, KIM127,Kimotab, Kinase Inhibitor 4SC, Kinase N, Kincort, Kindorase, Kineret,Kineto, Kitadol, Kitex, Kitolac, KLK1 Inhibitor, Klofen-L, Klotaren,KLS-40or, KLS-40ra, KM277, Knavon, Kodolo orabase, Kohakusanin, Koide,Koidexa, Kolbet, Konac, Kondro, Kondromin, Konshien, Kontab, Kordexa,Kosa, Kotase, KPE06001, KRP107, KRP203, KRX211, KRX252, KSB302, K-Sep,Kv 1.3 Blocker, Kv1.3 4SC, Kv1.3 inhibitor, KVK702, Kynol, L156602,Labizone, Labohydro, Labopen, Lacoxa, Lamin, Lamit, Lanfetil,laquinimod, larazotide acetate, LAS 186323, LAS 187247, LAS41002,Laticort, LBEC0101, LCP3301, LCP-Siro, LCP-Tacro, LCsA, LDP392, Leap-S,Ledercort, Lederfen, Lederlon, Lederspan, Lefenine, leflunomide, Leflux,Lefno, Lefra, Leftose, Lefumide, Lefunodin, Lefva, lenalidomide,lenercept, LentiRA, LEO15520, Leodase, Leukine, Leukocytefunction-associated antigen-1 antagonist, leukocyte immunoglobulin-likereceptor, subfamily A, member 4 antibody, Leukothera, leuprolideacetate, levalbuterol, levomenthol, LFA-1 Antagonist, LFA451, LFA703,LFA878, LG106, LG267 Inhibitors, LG688 Inhibitors, LGD5552, Li Life,LidaMantle, Lidex, lidocaine, lidocaine hydrochloride, Lignocainehydrochloride, LIM0723, LIM5310, Limethason, Limus, Limustin, Lindac,Linfonex, Linola acute, Lipcy, lisofylline, Listran, Liver X Receptormodulator, Lizak, LJP1207, LJP920, Lobafen, Lobu, Locafluo, Localyn,Locaseptil-Neo, Locpren, Lodine, Lodotra, Lofedic, Loflam, Lofnac,Lolcam, Lonac, lonazolac calcium, Loprofen, Loracort, Lorcam,Lorfenamin, Lorinden Lotio, Lorncrat, lornoxicam, Lorox, losmapimod,loteprednol etabonate, Loteprednol, Lotirac, Low Molecular GanodermaLucidum Polysaccharide, Loxafen, Loxfenine, Loxicam, Loxofen, Loxonal,Loxonin, loxoprofen sodium, Loxoron, LP183A1, LP183A2, LP204A1,LPCN1019, LT1942, LT1964, LTNS101, LTNS103, LTNS106, LTNS108, LTS1115,LTZMP001, Lubor, lumiracoxib, Lumitect, LX2311, LX2931, LX2932,LY2127399, LY2189102, LY2439821, LY294002, LY3009104, LY309887,LY333013, lymphocyte activation gene 3 antibody, Lymphoglobuline, Lyser,lysine aspirin, Lysobact, Lysoflam, Lysozyme hydrochloride, M3000, M834,M923, mAb hG-CSF, MABP1, macrophage migration inhibitory factorantibody, Maitongna, Majamil prolongatum, major histocompatibilitycomplex class II DR antibody, major histocompatibility complex class IIantibody, Malidens, Malival, mannan-binding lectin, mannan-bindinglectin-associated serine protease-2 antibody, MapKap Kinase 2 Inhibitor,maraviroc, Marlex, masitinib, Maso, MASP2 antibody, MAT304, MatrixMetalloprotease Inhibitor, mavrilimumab, Maxiflam, Maxilase, Maximums,Maxisona, Maxius, Maxpro, Maxrel, Maxsulid, Maxy12, Maxy30, MAXY4,Maxy735, Maxy740, Mayfenamic, MB11040, MBPY003b, MCAF5352A, McCam,McRofy, MCS18, MD707, MDAM, MDcort, MDR06155, MDT012, Mebicam, Mebuton,meclofenamate sodium, Meclophen, Mecox, Medacomb, Medafen, Medamol,Medesone, MEDI2070, MEDI5117, MEDI541, MEDI552, MEDI571, Medicox,Medifen, Medisolu, Medixon, Mednisol, Medrol, Medrolon,medroxyprogesterone acetate, Mefalgin, mefenamic acid, Mefenix,Mefentan, Meflen, Mefnetra forte, Meftagesic-DT, Meftal, MegakaryocyteGrowth and Development Factor, Megaspas, Megaster, megestrol acetate,Meite, Meksun, Melbrex, Melcam, Melcam, Melflam, Melic, Melica, Melix,Melocam, Melocox, Mel-One, Meloprol, Melosteral, Melox, Meloxan,Meloxcam, Meloxic, Meloxicam, Meloxifen, Meloxin, Meloxiv, Melpred,Melpros, Melurjin, Menamin, Menisone, Menthomketo, Menthoneurin,Mentocin, Mepa, Mepharen, meprednisone, Mepresso, Mepsolone,mercaptopurine, Mervan, Mesadoron, mesalamine, Mesasal, Mesatec,Mesenchymal Precursor Cells, mesenchymal stem cell, Mesipol, Mesren,Mesulan, Mesulid, Metacin, Metadaxan, Metaflex, Metalcaptase,metalloenzyme inhibitors, Metapred, Metax, Metaz, Meted, Metedic,Methacin, Methaderm, Methasone, Methotrax, methotrexate, methotrexatesodium, Methpred, Methyl prednisolone acetate, methyl salicylate, methylsulphonyl methane, Methylon, Methylpred, methylprednisolone,methylprednisolone acetate, methylprednisolone sodium succinate,methylprednisolone succinate, Methylprednisolone, Methysol, Metindol,Metoart, Metoject, Metolate, Metoral, Metosyn, Metotab, Metracin,Metrex, metronidazole, Metypred, Mevamox, Mevedal, Mevilox, Mevin SR,Mexilal, Mexpharm, Mext, Mextran, MF280, M-FasL, MHC class II beta chainpeptide, Micar, Miclofen, Miclofenac, Micofenolato Mofetil, Micosone,Microdase, microRNA 181a-2 oligonucleotide, MIF Inhibitors, MIFQb,MIKA-Ketoprofen, Mikametan, milodistim, Miltax, Minafen, Minalfen,Minalfene, Minesulin, Minocort, Mioflex, Miolox, Miprofen, Miridacin,Mirloks, Misoclo, Misofenac, MISTB03, MISTB04, Mitilor, mizoribine,MK0359, MK0812, MK0873, MK2 Inhibitors, MK50, MK8457, MK8808, MKC204,MLN0002, MLN0415, MLN1202, MLN273, MLN3126, MLN3701, MLN3897, MLNM002,MM093, MM7XX, MN8001, Mobic, Mobicam, Mobicox, Mobifen Plus, Mobilat,Mobitil, Mocox, Modigraf, Modrasone, Modulin, Mofecept, Mofetyl,mofezolac sodium, Mofilet, Molace, molgramostim, Molslide, Momekin,Momen Gele, Moment 100, Momesone, Momesun, Mometamed, mometasone,mometasone furoate, Monimate, monosodium alpha-luminol, Mopik, MOR103,MOR104, MOR105, MOR208 antibody, MORAb022, Moricam, morniflumate,Mosuolit, Motoral, Movaxin, Mover, Movex, Movix, Movoxicam, Mox Forte,Moxen, moxifloxacin hydrochloride, Mozobil, MP, MP0210, MP0270, MP1000,MP1031, MP196, MP435, MPA, mPGES-1 inhibitor, MPSS, MRX7EAT, MSL, MT203,MT204, mTOR Inhibitor, MTRX1011A, Mucolase, Multicort, MultiStem,muramidase, muramidase, muramidase hydrochloride, muromonab-CD3, Muslax,Muspinil, Mutaze, Muvera, MX68, Mycept, Mycocell, Mycocept,Mycofenolatmofetil Actavis, Mycofet, Mycofit, Mycolate, Mycoldosa,Mycomun, Myconol, mycophenolate mofetil, mycophenolate sodium,mycophenolic acid, Mycotil, myeloid progenitor cells, Myfenax, Myfetil,Myfortic, Mygraft, Myochrysine, Myocrisin, Myprodol, Mysone,nab-Cyclosporine, Nabentac, nabiximols, Nabton, Nabuco, Nabucox,Nabuflam, Nabumet, nabumetone, Nabuton, Nac Plus, Nacta, Nacton, Nadium,Naklofen SR, NAL1207, NAL1216, NAL1219, NAL1268, NAL8202, Nalfon,Nalgesin S, namilumab, Namsafe, nandrolone, Nanocort, Nanogam, NanosomalTacrolimus, Napageln, Napilac, Naprelan, Napro, Naprodil, Napronax,Napropal, Naproson, Naprosyn, Naproval, Naprox, naproxen, naproxensodium, Naproxin, Naprozen, Narbon, Narexsin, Naril, Nasida,natalizumab, Naxdom, Naxen, Naxin, Nazovel, NC2300, ND07, NDC01352,Nebumetone, NecLipGCSF, Necsulide, Necsunim, Nelsid-S, Neo Clobenate,Neo Swiflox FC, Neocoflan, Neo-Drol, Neo-Eblimon, Neo-Hydro, Neoplanta,Neoporine, Neopreol, Neoprox, Neoral, Neotrexate, Neozen, Nepra,Nestacort, Neumega, Neupogen, Neuprex, Neurofenac, Neurogesic, Neurolab,Neuroteradol, Neuroxicam, Neutalin, neutrazumab, Neuzym, New Panazox,Newfenstop, NewGam, Newmafen, Newmatal, Newsicam, NEX1285, sFcRIIB,Nextomab, NF-kappaB Inhibitor, NF-kB inhibitor, NGD20001, NHP554B,NHP554P, NI0101 antibody, NI0401, NI0501 antibody, NI0701, NI071, NI1201antibody, NI1401, Nicip, Niconas, Nicool, NiCord, Nicox, Niflumate,Nigaz, Nikam, Nilitis, Nimace, Nimaid, Nimark-P, Nimaz, Nimcet Juicy,Nime, Nimed, Nimepast, nimesulide, Nimesulix, Nimesulon, Nimica Plus,Nimkul, Nimlin, Nimnat, Nimodol, Nimpidase, Nimsaid-S, Nimser, Nimsy-SP,Nimupep, Nimusol, Nimutal, Nimuwin, Nimvon-S, Nincort, Niofen, Nipan,Nipent, Nise, Nisolone, Nisopred, Nisoprex, Nisulid, nitazoxanide,Nitcon, nitric oxide, Nizhvisal B, Nizon, NL, NMR1947, NN8209, NN8210,NN8226, NN8555, NN8765, NN8828, NNC014100000100, NNC051869, Noak,Nodevex, Nodia, Nofenac, Noflagma, Noflam, Noflamen, Noflux,Non-antibacterial Tetracyclines, Nonpiron, Nopain, Normferon, Notpel,Notritis, Novacort, Novagent, Novarin, Novigesic, NOXA12, NOXD19, Noxen,Noxon, NPI1302a-3, NPI1342, NPI1387, NPI1390, NPRCS1, NPRCS2, NPRCS3,NPRCS4, NPRCS5, NPRCS6, NPS3, NPS4, nPT-ery, NU3450, nuclear factorNF-kappa-B p65 subunit oligonucleotide, Nucort, Nulojix, Numed-Plus,Nurokind Ortho, Nusone-H, Nutrikemia, Nuvion, NV07alpha, NX001,Nyclobate, Nyox, Nysa, Obarcort, OC002417, OC2286, ocaratuzumab,OCTSG815, Oedemase, Oedemase-D, ofatumumab, Ofgyl-O, Ofvista, OHR118,OKi, Okifen, Oksamen, Olai, olokizumab, Omeprose E, Omnacortil, Omneed,Omniclor, Omnigel, Omniwel, onercept, ONO4057, ONS1210, ONS1220, OntacPlus, Ontak, ONX0914, OPC6535, opebacan, OPN101, OPN201, OPN302, OPN305,OPN401, oprelvekin, OPT66, Optifer, Optiflur, OptiMIRA, Orabase Hca,Oradexon, Oraflex, OralFenac, Oralog, Oralpred, Ora-sed, Orasone, orBec,Orbone forte, Orcl, ORE10002, ORE10002, Orencia, Org214007, Org217993,Org219517, Org223119, Org37663, Org39141, Org48762, Org48775, Orgadrone,Ormoxen, Orofen Plus, Oromylase Biogaran, Orthal Forte, Ortho Flex,Orthoclone OKT3, Orthofen, Orthoflam, Orthogesic, Orthoglu, Ortho-II,Orthomac, Ortho-Plus, Ortinims, Ortofen, Orudis, Oruvail, OS2, Oscart,Osmetone, Ospain, Ossilife, Ostelox, Osteluc, Osteocerin, osteopontin,Osteral, otelixizumab, Otipax, Ou Ning, OvaSave, OX40 Ligand Antibody,Oxa, Oxagesic CB, Oxalgin DP, oxaprozin, OXCQ, Oxeno, Oxib MD, Oxibut,Oxicam, Oxiklorin, Oximal, Oxynal, oxyphenbutazone, Oxyphenbutazone,ozoralizumab, P13 peptide, P1639, P21, P2X7 Antagonists, p38 AlphaInhibitor, p38 Antagonist, p38 MAP kinase inhibitor, p38alpha MAP KinaseInhibitor, P7 peptide, P7170, P979, PA401, PA517, Pabi-dexamethasone,PAC, PAC10649, paclitaxel, Painoxam, Paldon, Palima, pamapimod,Pamatase, Panafcort, Panafcortelone, Panewin, PanGraf, Panimun Bioral,Panmesone, Panodin SR, Panslay, Panzem, Panzem NCD, PAP1, papain,Papirzin, Pappen K Pap, Paptinim-D, paquinimod, PAR2 Antagonist,Paracetamol, Paradic, Parafen TAJ, Paramidin, Paranac, Parapar, Parci,parecoxib, Parixam, Parry-S, Partaject Busulfan, pateclizumab, Paxceed,PB10032, PBI1101, PBI1308, PBI1393, PBI1607, PBI1737, PBI2856, PBI4419,PBI4419, P-Cam, PCI31523, PCI32765, PCI34051, PCI45261, PCI45292,PCI45308, PD360324, PD360324, PDA001, PDE4 inhibitor, PDE-IV Inhibitor,PDL241 antibody, PDL252, Pediapred, Pefree, pegacaristim, Peganix,Peg-Interleukin 12, pegsunercept, Pegsunercept, PEGylated argininedeiminase, peldesine, pelubiprofen, Penacle, penicillamine, Penostop,Pentalgin, Pentasa, Pentaud, pentostatin, Peon, Pepdase, Pepser,Peptirase, Pepzen, Pepzol, Percutalgine, Periochip, PeroxisomeProliferator Activated Receptor gamma modulators, Petizene, PF00344600,PF04171327, PF04236921, PF04308515, PF05230905, PF05280586, PF251802,PF3475952, PF3491390, PF3644022, PF4629991, PF4856880, PF5212367,PF5230896, PF547659, PF755616, PF9184, PG27, PG562, PG760564, PG8395,PGE3935199, PGE527667, PH5, PH797804, PHA408, Pharmaniaga Mefenamicacid, Pharmaniaga Meloxicam, Pheldin, Phenocept, phenylbutazone, PHY702,PI3K delta inhibitor, PI3K Gamma/Delta Inhibitor, PI3K Inhibitor,Picalm, pidotimod, piketoprofen, Pilelife, Pilopil, Pilovate,pimecrolimus, Pipethanen, Piractam, Pirexyl, Pirobet, Piroc, Pirocam,Pirofel, Pirogel, Piromed, Pirosol, Pirox, Piroxen, Piroxicam, piroxicambetadex, Piroxifar, Piroxil, Piroxim, Pixim, Pixykine, PKC ThetaInhibitor, PL3100, PL5100 Diclofenac, Placenta Polypeptide, Plaquenil,plerixafor, Plocfen, PLR14, PLR18, Plutin, PLX3397, PLX5622, PLX647,PLX-BMT, pms-Diclofenac, pms-Ibuprofen, pms-Leflunomide, pms-Meloxicam,pms-Piroxicam, pms-Prednisolone, pms-Sulfasalazine, pms-Tiaprofenic,PMX53, PN0615, PN100, PN951, podofilox, POL6326, Polcortolon, Polyderm,Polygam S/D, Polyphlogin, Poncif, Ponstan, Ponstil Forte, Porine-ANeoral, Potaba, potassium aminobenzoate, Potencort, Povidone, povidoneiodine, pralnacasan, Prandin, Prebel, Precodil, Precortisyl Forte,Precortyl, Predfoam, Predicort, Predicorten, Predilab, Predilone,Predmetil, Predmix, Predna, Prednesol, Predni, prednicarbate,Prednicort, Prednidib, Prednifarma, Prednilasca, prednisolone,prednisolone acetate, prednisolone sodium phosphate, prednisolone sodiumsuccinate, prednisolone sodium succinate, prednisone, prednisoneacetate, Prednitop, Prednol-L, Prednox, Predone, Predonema, Predsol,Predsolone, Predsone, Predval, Preflam, Prelon, Prenaxol, Prenolone,Preservex, Preservin, Presol, Preson, Prexige, Priliximab, Primacort,Primmuno, Primofenac, prinaberel, Privigen, Prixam, Probuxil, Procarne,Prochymal, Procider-EF, Proctocir, Prodase, Prodel B, Prodent, ProdentVerde, Proepa, Profecom, Profenac L, Profenid, Profenol, Proflam,Proflex, Progesic Z, proglumetacin, proglumetacin maleate, Prograf,Prolase, Prolixan, promethazine hydrochloride, Promostem, Promune,PronaB, pronase, Pronat, Prongs, Pronison, Prontoflam, Propaderm-L,Propodezas, Propolisol, Proponol, propyl nicotinate, Prostaloc,Prostapol, Protacin, Protase, Protease Inhibitors, Protectan, ProteinaseActivated Receptor 2 Inhibitor, Protofen, Protrin, Proxalyoc, Proxidol,Proxigel, Proxil, Proxym, Prozym, PRT062070, PRT2607, PRTX100, PRTX200,PRX106, PRX167700, Prysolone, PS031291, PS375179, PS386113, PS540446,PS608504, PS826957, PS873266, Psorid, PT, PT17, PTL101, P-TransferFactor peptides, PTX3, Pulminiq, Pulsonid, Purazen, Pursin, PVS40200,PX101, PX106491, PX114, PXS2000, PXS2076, PYM60001, Pyralvex, Pyranim,pyrazinobutazone, Pyrenol, Pyricam, Pyrodex, Pyroxi-Kid, QAX576,Qianbobiyan, QPI1002, QR440, qT3, Quiacort, Quidofil, R107s, R125224,R1295, R132811, R1487, R1503, R1524, R1628, R333, R348, R548, R7277,R788, rabeximod, Radix Isatidis, Radofen, Raipeck, Rambazole, Randazima,Rapacan, Rapamune, Raptiva, Ravax, Rayos, RDEA119, RDEA436, RDP58,Reactine, Rebif, REC200, Recartix-DN, receptor for advanced glycationend products antibody, Reclast, Reclofen, recombinant HSA-TIMP-2,recombinant human alkaline Phosphatase, recombinant Interferon Gamma,Recominant human alkaline phosphatase, Reconil, Rectagel HC, Recticin,Recto Menaderm, Rectos, Redipred, Redolet, Refastin, Regenica, REGN88,Relafen, Relaxib, Relev, Relex, Relifen, Relifex, Relitch, Rematof,remestemcel-1, Remesulidum, Remicade, Remsima, Remsima, Remsima,ReN1869, Renacept, Renfor, Renodapt, Renodapt-S, Renta, Reosan,Repare-AR, Reparilexin, reparixin, Repertaxin, Repisprin, Resochin,Resol, resolvin El, Resurgil, Re-tin-colloid, Retoz, Reumacap, Reumacon,Reumadolor, Reumador, Reumanisal, Reumazin, Reumel, Reumotec, Reuquinol,revamilast, Revascor, Reviroc, Revlimid, Revmoksikam, Rewalk, Rexalgan,RG2077, RG3421, RG4934 antibody, RG7416, RG7624, Rheila, Rheoma,Rheprox, Rheudenolone, Rheufen, Rheugesic, Rheumacid, Rheumacort,Rheumatrex, Rheumesser, Rheumid, Rheumon, Rheumox, Rheuoxib, Rhewlin,Rhucin, RhuDex, Rhulef, Ribox, Ribunal, Ridaura, rifaximin, rilonacept,rimacalib, Rimase, Rimate, Rimatil, Rimesid, risedronate sodium,Ritamine, Rito, Rittman, rituximab, RNS60, RO1138452, Ro313948,RO3244794, RO5310074, Rob803, Rocamix, Rocas, Rofeb, rofecoxib, Rofee,Rofewal, Roficip Plus, Rojepen, Rokam, Rolodiquim, Romacox Fort,Romatim, romazarit, Ronaben, ronacaleret, Ronoxcin, ROR Gamma TAntagonist, ROR gamma t inverse agonists, Rosecin, rosiglitazone,Rosmarinic acid, Rotan, Rotec, Rothacin, Roxam, Roxib, Roxicam, Roxopro,Roxygin DT, RP54745, RPI78, RPI78M, RPI78MN, RPIMN, RQ00000007,RQ00000008, RTA402, R-Tyflam, Rubicalm, Rubifen, Ruma pap, Rumalef,Rumidol, Rumifen, Runomex, rusalatide acetate, ruxolitinib, RWJ445380,RX10001, Rycloser MR, Rydol, S1P Receptor Agonists, S1P ReceptorModulators, S1P1 Agonist, S1P1 receptor agonist, S2474, S3013, SA237,SA6541, Saaz, S-adenosyl-L-methionine-sulfate-p-toluene sulfonate, Sala,Salazidin, Salazine, Salazopyrin, Salcon, Salicam, salsalate, Sameron,SAN300, Sanaven, Sandimmun, Sandoglobulin, Sanexon, SangCya, SAR153191,SAR302503, SAR479746, Sarapep, sargramostim, Sativex, Savantac, Save,Saxizon, Sazo, SB1578, SB210396, SB217969, SB242235, SB273005, SB281832,SB683698, SB751689, SBI087, SC080036, SC12267, SC409, Scaflam, SCDketoprofen, SCIO323, SCIO469, SD-15, SD281, SDP051 antibody, Sd-rxRNA,secukinumab, Sedase, Sedilax, Sefdene, Seizyme, SEL113, Seladin,Selecox, selectin P ligand antibody, Glucocorticoid Receptor Agonist,Selectofen, Selektine, SelK1 antibody, Seloxx, Selspot, Selzen,Selzenta, Selzentry, semapimod, semapimod hydrochloride, semparatide,Semparatide, Senafen, Sendipen, Senterlic, SEP119249, Sepdase,Septirose, Seractil, Serafen-P, Serase, Seratid D, Seratiopeptidase,Serato-M, Seratoma Forte, Serazyme, Serezon, Sero, Serodase, Serpicam,Serra, serrapeptase, Serratin, Serratiopeptidase, Serrazyme, Servisone,Seven E P, SGI1252, SGN30, SGN70, SGX203, shark cartilage extract,Sheril, Shield, Shifazen, Shifazen-Fort, Shincort, Shincort, Shiosol,ShK186, Shuanghuangxiaoyan, SI615, SI636, Sigmasporin, Sigmasporin,SIM916, Simpone, Simulect, Sinacort, Sinalgia, Sinapol, Sinatrol,Sinsia, siponimod, Sirolim, sirolimus, Siropan, Sirota, Sirova,sirukumab, Sistal Forte, SKF105685, SKF105809, SKF106615, SKF86002,Skinalar, Skynim, Skytrip, SLAM family member 7 antibody, Slo-indo,SM101, SM201 antibody, SM401, SMAD family member 7 oligonucleotide,SMART Anti-IL-12 Antibody, SMP114, SNO030908, SNO070131, sodiumaurothiomalate, sodium chondroitin sulfate, sodium deoxyribonucleotide,sodium gualenate, sodium naproxen, sodium salicylate, Sodixen, Sofeo,Soleton, Solhidrol, Solicam, Soliky, Soliris, Sol-Melcort, Solomet,Solondo, Solone, Solu-Cort, Solu-Cortef, Solu-Decortin H, Solufen,Solu-Ket, Solumark, Solu-Medrol, Solupred, Somalgen, somatropin, Sonap,Sone, sonepcizumab, Sonexa, Sonim, Sonim P, Soonil, Soral, Sorenil,sotrastaurin acetate, SP-10, SP600125, Spanidin, SP-Cortil, SPD550,Spedace, sperm adhesion molecule 1, Spictol, spleen tyrosine kinaseoligonucleotide, Sporin, S-prin, SPWF1501, SQ641, SQ922, SR318B, SR9025,SRT2104, SSR150106, SSR180575, SSS07 antibody, ST1959, STA5326, stabilin1 antibody, Stacort, Stalogesic, stanozolol, Staren, Starmelox, StedexIND-SWIFT, Stelara, Stemin, Stenirol, Sterapred, Steriderm S, Steno,Sterisone, Steron, stichodactyla helianthus peptide, Stickzenol A,Stiefcortil, Stimulan, STNM01, Store Operated Calcium Channel (SOCC)Modulator, STP432, STP900, Stratasin, Stridimmune, Strigraf, SU Medrol,Subreum, Subuton, Succicort, Succimed, Sulan, Sulcolon, SulfasalazinHeyl, Sulfasalazin, sulfasalazine, Sulfovit, Sulidac, Sulide, sulindac,Sulindex, Sulinton, Sulphafine, Sumilu, SUN597, Suprafen, Supretic,Supsidine, Surgam, Surgamine, Surugamu, Suspen, Suton, Suvenyl, Suwei,SW Dexasone, Syk Family Kinase Inhibitor, Syn1002, Synacran, Synacthen,Synalar C, Synalar, Synavive, Synercort, Sypresta, T cellcytokine-inducing surface molecule antibody, T cell receptor antibody,T5224, T5226, TA101, TA112, TA383, TA5493, tabalumab, Tacedin, Tacgraf,TACIFcS, Tacrobell, Tacrograf, Tacrol, tacrolimus, Tadekinig alpha,Tadolak, TAFA93, Tafirol Arno, Taizen, TAK603, TAK715, TAK783, Takfa,Taksta, talarozole, Talfin, Talmain, talmapimod, Talmea, Talnif,talniflumate, Talos, Talpain, Talumat, Tamalgen, Tamceton, Tamezon,Tandrilax, tannins, Tannosynt, Tantum, tanzisertib, Tapain-beta,Tapoein, Tarenac, tarenflurbil, Tarimus, Tarproxen, Tauxib, Tazomust,TBR652, TC5619, T-cell, immune regulator 1, ATPase, H+ transporting,lysosomal V0 subunit A3 antibody, TCK1, T-cort, T-Dexa, Tecelac, Tecon,teduglutide, Teecort, Tegeline, Tementil, temoporfin, Tencam, Tendrone,Tenefuse, Tenfly, tenidap sodium, Tenocam, Tenoflex, Tenoksan, Tenotil,tenoxicam, Tenoxim, Tepadina, Teracort, Teradol, tetomilast, TG0054,TG1060, TG20, TG20, tgAAC94, Th1/Th2 Cytokine Synthase Inhibitor, Th-17cell inhibitors, Thalido, thalidomide, Thalomid, Themisera, Thenil,Therafectin, Therapyace, thiarabine, Thiazolopyrimidines, thioctic acid,thiotepa, THR090717, THR0921, Threenofen, Thrombate III, Thymic peptide,Thymodepressin, Thymogam, Thymoglobulin, Thymoglobuline, Thymojectthymic peptides, thymomodulin, thymopentin, thymopolypetides,tiaprofenic acid, tibezonium iodide, Ticoflex, tilmacoxib, Tilur,T-immune, Timocon, Tiorase, Tissop, TKB662, TL011, TLR4 antagonists,TLR8 inhibitor, TM120, TM400, TMX302, TNF Alpha inhibitor, TNF alpha-TNFreceptor antagonist, TNF antibody, TNF receptor superfamily antagonists,TNF TWEAK Bi-Specific, TNF-Kinoid, TNFQb, TNFR1 antagonist, TNR001,TNX100, TNX224, TNX336, TNX558, tocilizumab, tofacitinib, Tokuhon happ,TOL101, TOL102, Tolectin, ToleriMab, Tolerostem, Tolindol, toll-likereceptor 4 antibody, toll-like receptor antibody, tolmetin sodium,Tongkeeper, Tonmex, Topflame, Topicort, Topleucon, Topnac, ToppinIchthammol, toralizumab, Toraren, Torcoxia, Toroxx, Tory, Toselac,Totaryl, Touch-med, Touchron, Tovok, Toxic apis, Toyolyzom, TP4179,TPCA1, TPI526, TR14035, Tradil Fort, Traficet-EN, Tramace, tramadolhydrochloride, tranilast, Transimune, Transporina, Tratul, Trexall,Triacort, Triakort, Trialon, Triam, triamcinolone, triamcinoloneacetate, triamcinolone acetonide, triamcinolone acetonide acetate,triamcinolone hexacetonide, Triamcort, Triamsicort, Trianex, Tricin,Tricort, Tricortone, TricOs T, Triderm, Trilac, Trilisate, Trinocort,Trinolone, Triolex, triptolide, Trisfen, Trivaris, TRK170, TRK530,Trocade, trolamine salicylate, Trolovol, Trosera, Trosera D, Troycort,TRX1 antibody, TRX4, Trymoto, Trymoto-A, TT301, TT302, TT32, TT32, TT33,TTI314, tumor necrosis factor, tumor necrosis factor 2-methoxyethylphosphorothioate oligonucleotide, tumor necrosis factor antibody, tumornecrosis factor kinoid, tumor necrosis factor oligonucleotide, tumornecrosis factor receptor superfamily, member 1B antibody, tumor necrosisfactor receptor superfamilylB oligonucleotide, tumor necrosis factorsuperfamily, member 12 antibody, tumor necrosis factor superfamily,member 4 antibody, tumor protein p53 oligonucleotide, tumour necrosisfactor alpha antibody, TuNEX, TXA127, TX-RAD, TYK2 inhibitors, Tysabri,ubidecarenone, Ucerase, ulodesine, Ultiflam, Ultrafastin, Ultrafen,Ultralan, U-Nice-B, Uniplus, Unitrexate, Unizen, Uphaxicam, UR13870,UR5269, UR67767, Uremol-HC, Urigon, U-Ritis, ustekinumab, V85546,Valcib, Valcox, valdecoxib, Valdez, Valdixx, Valdy, Valentac, Valoxib,Valtune, Valus AT, Valz, Valzer, Vamid, Vantal, Vantelin, VAP-1 SSAOInhibitor, vapaliximab, varespladib methyl, Varicosin, Varidase,vascular adhesion protein-1 antibody, VB110, VB120, VB201, VBY285,Vectra-P, vedolizumab, Vefren, VEGFR-1 Antibody, Veldona, veltuzumab,Vendexine, Venimmun N, Venoforte, Venoglobulin-IH, Venozel, Veral,Verax, vercirnon, vero-Dexamethasone, Vero-Kladribin, Vetazone, VGX1027,VGX750, Vibex MTX, vidofludimus, Vifenac, Vimovo, Vimultisa, Vincort,Vingraf, Vioform-HC, Vioxl, Vioxx, Virobron, visilizumab, Vivaglobin,Vivalde Plus, Vivian-A, VLST002, VLST003, VLST004, VLST005, VLST007,Voalla, voclosporin, Vokam, Vokmor, Volmax, Volna-K, Voltadol,Voltagesic, Voltanase, Voltanec, Voltaren, Voltarile, Voltic, Voren,vorsetuzumab, Votan-SR, VR909, VRA002, VRP1008, VRS826, VRS826, VT111,VT214, VT224, VT310, VT346, VT362, VTX763, Vurdon, VX30 antibody, VX467,VX5, VX509, VX702, VX740, VX745, VX745, VX850, W54011, Walacort, Walix,WC3027, Wilgraf, Winflam, Winmol, Winpred, Winsolve, Wintogeno, WIP901,Woncox, WSB711 antibody, WSB712 antibody, WSB735, WSB961, X071NAB,X083NAB, Xantomicin Forte, Xedenol, Xefo, Xefocam, Xenar, Xepol, X-Flam,Xibra, Xicam, Xicotil, Xifaxan, XL499, XmAb5483, XmAb5485, XmAb5574,XmAb5871, XOMA052, Xpress, XPro1595, XtendTNF, XToll, Xtra, Xylex-H,Xynofen SR, Yang Shu-IVIG, YHB14112, YM974, Youfeline, Youfenac, Yuma,Yumerol, Yuroben, YY piroxicam, Z104657A, Zacy, Zaltokin, zaltoprofen,Zap70 Inhibitor, Zeepain, Zeloxim Fort, Zema-Pak, Zempack, Zempred,Zenapax, Zenas, Zenol, Zenos, Zenoxone, Zerax, Zerocam, Zerospasm, ZFNs,zinc oxide, Zipsor, ziralimumab, Zitis, Zix-S, Zocort, Zodixam,Zoftadex, zoledronic acid, Zolfin, Zolterol, Zopyrin, Zoralone, ZORprin,Zortress, ZP1848, zucapsaicin, Zunovate, Zwitterionic polysaccharides,ZY1400, Zybodies, Zycel, Zyrofen, Zyrogen Inhibitors, Zyser, Zytrim, andZywin-Forte. In addition, the anti-inflammatory drugs, as listed above,may be combined with one or more agents listed above or herein or withother agents known in the art.

In one embodiment, a drug that reduces, inhibits, prevents and/orameliorates inflammation, for example, one of the drugs provided above,is delivered to the suprachoroidal space of the eye using themicroneedle devices and methods disclosed herein, and is used to treat,prevent and/or ameliorate a disease or disorder selected from arthritis,degenerative arthritis, psoriatic arthritis, arthritic disorders,arthritic pain, arthrosis, autoimmune arthritis, autoimmune diseases,autoimmune disorders, axial spondyloarthritis, chronic prosthetic jointinfection, collagen induced arthritis, osteoarthritis, rheumatoidarthritis, senile arthritis, seronegative oligoarthritis of the knee,allergic and autoimmune inflammatory diseases, inflammatory diseases,inflammatory disorders, collagen diseases, discoid Lupus Erythematosus,immune deficiencies, immune diseases, immune disorders, immunodeficiencydiseases, immunodeficiency disorders, immunoglobulin (IgG2) deficiency,immunoglobulin deficiency, Inflammation, Lambert-Eaton myastheniasyndrome, polymyositis, dermatomyositis, polyneuritis, post-operativeocular inflammation, polychondritis, sporadic inclusion body myositis,Systemic Lupus Erythematosus, T cell deficiency, TNF-receptor associatedperiodic syndrome, tropical spastic paraparesis, Wegener Granulomatosis,X-linked severe combined immunodeficiency disease, Behcet's disease,Crohn's disease, Crohn's Fistula, cutaneous Lupus Erythematosus, acuteinflammation, acute inflammatory edema, adrenocortical insufficiency,cerebral inflammation, chronic lung inflammation, corticoid-responsiveinflammatory skin disorders, cutaneous inflammation, dermalinflammation, dry skin inflammatory disease, ear edema, earinflammation, glossitis, inflammatory bowel disease, inflammatorydegenerative disease, inflammatory disorders of the eye and/or ear,inflammatory lesions in fungal infections, inflammatory lesions,inflammatory pain, inflammatory skin diseases or disorders, mouth andgum inflammation, mouth and throat inflammation, musculoskeletaldisorders, otitis, pelvic inflammatory disease, perianal inflammation,post operative inflammation, pulmonary inflammation, rectalinflammation, refractory idiopathic inflammatory myopathies, seborrhoeicdermatitis, swelling, aphthous ulcerations, chronic polyarthritis,juvenile rheumatoid arthritis, rheumatic diseases, Sjogren's syndrome,opthalmic for Sjogren's syndrome, transplant rejection, acute allograftrejection, chronic graft rejection, graft versus host disease, humoralrejection in heart transplantation, humoral rejection in kidneytransplantation, organ rejection in renal transplantation, solid organtransplant rejection, bronchiolitis obliterans after lungtransplantation, rejection of bone marrow transplant, chronic lungtransplant rejection, Corneal graft rejection, delayed graft function inkidney transplantation, heart transplant rejection, Homotransplantationrejection, immune rejection of hESC-derived therapeutic grafts, kidneytransplant rejection, liver transplant rejection, lung transplantrejection, organ rejection, pancreatic islet transplantation rejectionin type I diabetes, renal transplant rejection and xenograft rejection.

In one embodiment, the drug delivered to the suprachoroidal space usingthe microneedle devices and methods disclosed herein treats, prevents,and/or ameliorates macular degeneration (e.g., age related maculardegeneration, dry age related macular degeneration, exudativeage-related macular degeneration, geographic atrophy associated with agerelated macular degeneration, neovascular (wet) age-related maculardegeneration, neovascular maculopathy and age related maculardegeneration, occult with no classic choroidal neovascularization (CNV)in age-related macular degeneration, Stargardt's disease, Subfoveal wetAge-Related macular degeneration, and Vitreomacular Adhesion (VMA)associated with Neovascular Age Related macular degeneration). Examplesof drugs that treat, prevent and/or ameliorate macular degeneration thatcan be used in conjunction with the devices and methods described hereininclude, but are not limited to: A0003, A36 peptide, AAV2-sFLT01,ACE041, ACU02, ACU3223, ACU4429, AdPEDF, aflibercept, AG13958,aganirsen, AGN150998, AGN745, AL39324, AL78898A, AL8309B, ALN-VEG01,alprostadil, AM1101, amyloid beta antibody, anecortave acetate,Anti-VEGFR-2 Alterase, Aptocine, APX003, ARC1905, ARC1905 with Lucentis,ATG3, ATP-binding cassette, sub-family A, member 4 gene, ATXS10, Avastinwith Visudyne, AVT101, AVT2, bertilimumab, bevacizumab with verteporfin,bevasiranib sodium, bevasiranib sodium; with ranibizumab, brimonidinetartrate, BVA301, canakinumab, Cand5, Cand5 with Lucentis, CERE140,ciliary neurotrophic factor, CLT009, CNT02476, collagen monoclonalantibody, complement component 5 aptamer (pegylated), complementcomponent 5 aptamer (pegylated) with ranibizumab, complement componentC3, complement factor B antibody, complement factor D antibody, copperoxide with lutein, vitamin C, vitamin E, and zinc oxide, dalantercept,DE109, dexamethasone with ranibizumab and verteporfin, disitertide, DNAdamage inducible transcript 4 oligonucleotide, E10030, E10030 withLucentis, EC400, eculizumab, EGP, EHT204, embryonic stem cells, humanstem cells, endoglin monoclonal antibody, EphB4 RTK Inhibitor, EphB4Soluble Receptor, ESBA1008, ETX6991, Evizon, Eyebar, EyePromise Five,Eyevi, Eylea, F200, FCFD4514S, fenretinide, fluocinolone acetonide,fluocinolone acetonide with ranibizumab, fms-related tyrosine kinase 1oligonucleotide, fms-related tyrosine kinase 1 oligonucleotide withkinase insert domain receptor 169, fosbretabulin tromethamine, Gamunex,GEM220, GS101, GSK933776, HC31496, Human n-CoDeR, HYB676, IBI-20089 withLucentis, iCo-008, Iconl, I-Gold, Ilaris, Iluvien, Iluvien withLucentis, immunoglobulins, integrin alpha5beta1 immunoglobulinfragments, Integrin inhibitor, IRIS Lutein, I-Sense Ocushield, Isonep,isopropyl unoprostone, JPE1375, JSM6427, KH902, LentiVue, LFG316, LP590,LPO1010AM, Lucentis, Lucentis with Visudyne, Lutein ekstra, Lutein withmyrtillus extract, Lutein with zeaxanthin, M200, M200 with Lucentis,Macugen, MC1101, MCT355, mecamylamine, Microplasmin, motexafin lutetium,MP0112, NADPH oxidase inhibitors, Neoretna, neurotrophin 4 gene,Nova21012, Nova21013, NT501, NT503, Nutri-Stulln, ocriplasmin, OcuXan,Oftan Macula, Optrin, ORA102 with Avastin, P144, P17, Palomid 529,PAN90806, Panzem, Panzem, PARP Inhibitors, pazopanib hydrochloride,pegaptanib sodium, PF4523655, PG11047, piribedil, platelet-derivedgrowth factor beta polypeptide aptamer (pegylated), platelet-derivedgrowth factor beta polypeptide aptamer (pegylated) with ranibizumab,PLG101, PMX20005, PMX53, POT4, PRS055, PTK787, ranibizumab, ranibizumabwith triamcinolone acetonide, ranibizumabwith verteporfin, ranibizumabwith volociximab, RD27, Rescula, Retaane, retinal pigment epithelialcells, RetinoStat, RG7417, RN6G, RT101, RTU007, SB267268, serpinpeptidase inhibitor, clade F, member 1 gene, shark cartilage extract,Shef1, SIR1046, SIR1076, Sirna027, sirolimus, SMTD004, Snelvit, SODMimetics, Soliris, sonepcizumab, squalamine lactate, ST602, StarGen,T2TrpRS, TA106, talaporfin sodium, Tauroursodeoxycholic acid, TG100801,TKI, TLCx99, TRC093, TRC105, triamcinolone acetonide with verteporfin,Trivastal Retard, TT30, Ursa, ursodiol, Vangiolux, VAR10200, vascularendothelial growth factor antibody, vascular endothelial growth factorB, vascular endothelial growth factor kinoid, vascular endothelialgrowth factor oligonucleotide, VAST Compounds, vatalanib, VEGFInhibitor, verteporfin, Visudyne, Visudyne with Lucentis anddexamethasone, Visudyne with triamcinolone acetonide, Vivis,volociximab, Votrient, XV615, zeaxanthin, ZFP TF, zinc-monocysteine andZybrestat. In one embodiment, one or more of the macular degenerationtreating drugs described above is combined with one or more agentslisted above or herein or with other agents known in the art.

In one embodiment, the methods and devices provided hererin are used todelivery triamcinolone or triamcinolone acetonide to the suprachoroidalspace of an eye of a patient in need thereof. In a further embodiment,the triamcinolone or triamcinolone acetonide is delivered for thetreatment of sympathetic ophthalmia, temporal arteritis, uveitis and/orocular inflammatory conditions. In one embodiment, triamcinolone ortriamcinolone acetonide is delivered to the suprachoroidal space of theeye in a patient in need of treatment of sympathetic opthalmia with themethods and devices described herein. In another embodiment,triamcinolone or triamcinolone acetonide is delivered to thesuprachoroidal space of the eye in a patient in need of treatment oftemporal arteritis with the methods and devices described herein. In yetanother embodiment, triamcinolone or triamcinolone acetonide isdelivered to the suprachoroidalspace of the eye in a patient in need oftreatment of uveitis, with the methods and devices described herein. Inanother embodiment, triamcinolone or triamcinolone acetonide isdelivered to the suprachoroidal space of the eye in a patient in need oftreatment of one or more ocular inflammatory conditions, with themethods and devices described herein.

The triamcinolone composition provided herein, in one embodiment, is asuspension comprising microparticles or nanoparticles of triamcinoloneor triamcinolone acetonide. The microparticles, in one embodiment, havea D50 of about 3 μm or less. In a further embodiment, the D₅₀ is about 2μm. In another embodiment, the D50 is about 2 μm or less. In evenanother embodiment, the D50 is about 1000 nm or less. Themicroparticles, in one embodiment, have a D₉₉ of about 10 μm or less. Inanother embodiment, the D₉₉ is about 10 μm. In another embodiment, theD₉₉ is less than about 10 μm or less than about 9 μm or less.

In one embodiment, the triamcinolone composition comprises triamcinolonemicroparticles. In a further embodiment, the composition comprisespolysorbate 80. In another embodiment, the triamcinolone compositioncomprises one or more of CaCl₂, MgCl₂, sodium acetate and sodiumcitrate. In one embodiment, the composition comprises polysorbate 80 ata w/v % of 0.02% or about 0.02%, 0.015% or about 0.015%.

In certain embodiments the drug delivered to ocular tissues using themicroneedle devices and methods disclosed herein treats, prevents,and/or ameliorates fibrosis (e.g. myelofibrosis, fibrosis in diabeticnephropathy, cystic fibrosis, scarring, and skin fibrosis).

In one embodiment, a drug that treats, prevents and/or amelioratesfibrosis is used in conjunction with the devices and methods describedherein, and is delivered to the suprachoroidal space of the eye. In afurther embodiment, the drug is Actimmune with Pirfenidone, ACUHTR028,AlphaVBeta5, aminobenzoate potassium, amyloid P, ANG1122, ANG1170,ANG3062, ANG3281, ANG3298, ANG4011, Anti-CTGF RNAi, Aplidin, astragalusmembranaceus extract with salvia and schisandra chinensis,atherosclerotic plaque blocker, Azol, AZX100, BB3, connective tissuegrowth factor antibody, CT140, danazol, Esbriet, EXC001, EXC002, EXC003,EXC004, EXC005, F647, FG3019, Fibrocorin, Follistatin, FT011, Galectin-3inhibitors, GKT137831, GMCT01, GMCT02, GRMD01, GRMD02, GRN510, HeberonAlfa R, interferon alfa-2b, interferon gamma-1b with pirfenidone,ITMN520, JKB119, JKB121, JKB122, KRX168, LPA1 receptor antagonist,MGN4220, MIA2, microRNA 29a oligonucleotide, MMI0100, noscapine,PBI4050, PBI4419, PDGFR inhibitor, PF-06473871, PGN0052, Pirespa,Pirfenex, pirfenidone, plitidepsin, PRM151, Px102, PYN17, PYN22 withPYN17, Relivergen, rhPTX2 Fusion Proteins, RXI109, secretin, STX100,TGF-beta Inhibitor, transforming growth factor, beta receptor 2oligonucleotide, VA999260 or XV615. In one embodiment, one or more ofthe fibrosis treating drugs described above is combined with one or moreagents listed above or herein or with other agents known in the art.

In one embodiment, a drug that treats, prevents and/or amelioratesdiabetic macular edema is used in conjunction with the devices andmethods described herein, and is delivered to the suprachoroidal spaceof the eye. In a further embodiment, the drug is AKB9778, bevasiranibsodium, Cand5, choline fenofibrate, Cortiject, c-raf 2-methoxyethylphosphorothioate oligonucleotide, DE109, dexamethasone, DNA damageinducible transcript 4 oligonucleotide, FOV2304, iCo007, KH902, MP0112,NCX434, Optina, Ozurdex, PF4523655, SAR1118, sirolimus, SK0503 orTriLipix. In one embodiment, one or more of the diabetic macular edematreating drugs described above is combined with one or more agentslisted above or herein or with other agents known in the art.

In one embodiment, a drug that treats, prevents and/or amelioratesmacular edema is used in conjunction with the devices and methodsdescribed herein, and is delivered to the suprachoroidal space of theeye. In a further embodiment, the drug is denufosol tetrasodium,dexamethasone, ecallantide, pegaptanib sodium, ranibizumab ortriamcinolone. In addition, the drugs delivered to ocular tissues usingthe microneedle devices and methods disclosed herein which treat,prevent, and/or ameliorate macular edema, as listed above, may becombined with one or more agents listed above or herein or with otheragents known in the art.

In one embodiment, a drug that treats, prevents and/or amelioratesocular hypertension is used in conjunction with the devices and methodsdescribed herein and is delivered to the suprachoroidal space of theeye. In a further embodiment, the drug is 2-MeS-beta gamma-CC12-ATP,Aceta Diazol, acetazolamide, Aristomol, Arteoptic, AZD4017, Betalmic,betaxolol hydrochloride, Betimol, Betoptic S, Brimodin, Brimonal,brimonidine, brimonidine tartrate, Brinidin, Calte, carteololhydrochloride, Cosopt, CS088, DE092, DE104, DE111, dorzolamide,dorzolamide hydrochloride, Dorzolamide hydrochloride with Timololmaleate, Droptimol, Fortinol, Glaumol, Hypadil, Ismotic, isopropylunoprostone, isosorbide, Latalux, latanoprost, Latanoprost with Timololmaleate, levobunolol hydrochloride, Lotensin, Mannigen, mannitol,metipranolol, mifepristone, Mikelan, Minims Metipranolol, Mirol,nipradilol, Nor Tenz, Ocupress, olmesartan, Ophtalol, pilocarpinenitrate, Piobaj, Rescula, RU486, Rysmon TG, SAD448, Saflutan, Shemol,Taflotan, tafluprost, tafluprost with timolol, Thiaboot, Timocomod,timolol, Timolol Actavis, timolol hemihydrate, timolol maleate, Travast,travoprost, Unilat, Xalacom, Xalatan or Zomilol. In addition, the drugsdelivered to ocular tissues using the microneedle devices and methodsdisclosed herein which treat, prevent, and/or ameliorate ocularhypertension, as listed above, may be combined with one or more agentslisted above or herein or with other agents known in the art.

In certain embodiments one or more drugs may be delivered to oculartissues and/or into the suprachoroidal space via the systems and devicesdescribed herein. Delivery of one or more drugs into the suprachoroidalspace using the microneedle device described herein may be accomplishedby using one or more microneedles. In addition, combinations of one ofmore drugs may be delivered to the suprachoroidal space using themicroneedle device described herein in combination with delivery of oneor more drugs via intravitreal (IVT) administration (e.g., intravitrealinjection, intravitreal implant or eye drops). Methods of IVTadministration are well known in the art. Examples of drugs that can beadministered via IVT include, but are not limited to: A0003, A0006,Acedolone, AdPEDF, aflibercept, AG13958, aganirsen, AGN208397, AKB9778,AL78898A, amyloid P, Angiogenesis Inhibitor Gene Therapy, ARC1905,Aurocort, bevasiranib sodium, brimonidine, Brimonidine, brimonidinetartrate, bromfenac sodium, Cand5, CERE140, Ciganclor, CLT001, CLT003,CLT004, CLT005, complement component 5 aptamer (pegylated), complementfactor D antibody, Cortiject, c-raf 2-methoxyethyl phosphorothioateoligonucleotide, cyclosporine, triamcinolone, DE109, denufosoltetrasodium, dexamethasone, dexamethasone phosphate, disitertide, DNAdamage inducible transcript 4 oligonucleotide, E10030, ecallantide,EG3306, Eos013, ESBA1008, ESBA105, Eylea, FCFD4514S, fluocinoloneacetonide, fms-related tyrosine kinase 1 oligonucleotide, fomivirsensodium, fosbretabulin tromethamine, FOV2301, FOV2501, ganciclovir,ganciclovir sodium, GS101, GS156, hyaluronidase, IBI20089, iCo007,Iluvien, INS37217, Isonep, JSM6427, Kalbitor, KH902, lerdelimumab,LFG316, Lucentis, M200, Macugen, Makyueido, Microplasmin, MK0140,MP0112, NCX434, neurotrophin 4 gene, OC10X, ocriplasmin, ORA102,Ozurdex, P144, P17, Palomid 529, pazopanib hydrochloride, pegaptanibsodium, Plasma Kallikrein Inhibitors, platelet-derived growth factorbeta polypeptide aptamer (pegylated), POT4, PRM167, PRS055, QPI1007,ranibizumab, resveratrol, Retilone, retinal pigment epithelium-specificprotein 65 kDa gene, Retisert, rod derived cone viability factor, RPE65Gene Therapy, RPGR Gene Therapy, RTP801, Sd-rxRNA, serpin peptidaseinhibitor clade F member 1 gene, Sirna027, sirolimus, sonepcizumab,SRT501, STP601, TG100948, Trabio, triamcinolone, triamcinoloneacetonide, Trivaris, tumor necrosis factor antibody, VEGF/rGel-Op,verteporfin, Visudyne, Vitrase, Vitrasert, Vitravene, Vitreals,volociximab, Votrient, XG102, Xibrom, XV615, and Zybrestat. Accordingly,the methods of the present invention include administrating via IVT oneor more of the drugs listed above in combination with one or more drugsdisclosed herein administered into the suprachoroidal space using themicroneedle device described herein.

In one embodiment, the drug is formulated for storage and delivery viathe microneedle device described herein. The “drug formulation” is aformulation of a drug, which typically includes one or morepharmaceutically acceptable excipient materials known in the art. Theterm “excipient” refers to any non-active ingredient of the formulationintended to facilitate handling, stability, dispersibility, wettability,release kinetics, and/or injection of the drug. In one embodiment, theexcipient may include or consist of water or saline.

In one embodiment, the fluid drug formulation includes microparticles ornanoparticles, each of which can include at least one drug. Desirably,the microparticles or nanoparticles provide for the controlled releaseof drug into the ocular tissue. As used herein, the term “microparticle”encompasses microspheres, microcapsules, microparticles, and beads,having a number average diameter of 1 to 100 μm, most preferably 1 to 25μm. The term “nanoparticles” are particles having a number averagediameter of 1 to 1000 nm. Microparticles may or may not be spherical inshape. “Microcapsules” are defined as microparticles having an outershell surrounding a core of another material. The core can be liquid,gel, solid, gas, or a combination thereof. In one case, the microcapsulemay be a “microbubble” having an outer shell surrounding a core of gas,wherein the drug is disposed on the surface of the outer shell, in theouter shell itself, or in the core. Microbubbles may respond to acousticvibrations as known in the art for diagnosis and/or can be used to burstthe microbubble to release its payload at/into a select ocular tissuesite. “Microspheres” can be solid spheres, can be porous and include asponge-like or honeycomb structure formed by pores or voids in a matrixmaterial or shell, or can include multiple discrete voids in a matrixmaterial or shell. The microparticle or nanoparticles may furtherinclude a matrix material. The shell or matrix material may be apolymer, amino acid, saccharride, or other material known in the art ofmicroencapsulation.

The drug-containing microparticles or nanoparticles may be suspended inan aqueous or non-aqueous liquid vehicle. The liquid vehicle may be apharmaceutically acceptable aqueous solution, and optionally may furtherinclude a surfactant. The microparticles or nanoparticles of drugthemselves may include an excipient material, such as a polymer, apolysaccharide, a surfactant, etc., which are known in the art tocontrol the kinetics of drug release from particles.

In one embodiment, the fluid drug formulation further includes an agenteffective to degrade collagen or GAG fibers in the sclera, which mayenhance penetration/release of the drug into the ocular tissues. Thisagent may be, for example, an enzyme, such a hyaluronidase, acollagenase, or a combination thereof. In a variation of this method,the enzyme is administered to the ocular tissue in a separate stepfrom—preceding or following—infusion of the drug. The enzyme and drugare administered at the same site.

In another embodiment, the drug formulation is one that undergoes aphase change upon administration. For instance, a liquid drugformulation may be injected through hollow microneedles into thesuprachoroidal space, where it then gels and the drug diffuses out fromthe gel for controlled release.

While the embodiments and methods herein describe delivering amedicament to a target tissue, the embodiments described herein can beconfigured to facilitate a biopsy procedure and/or removal of asubstance from a target location.

While the embodiments have been described above in use on ocular tissue,in some instances, the embodiments and methods described herein can beused on any other suitable bodily tissue. For example, in someinstances, the use of an adjustable length needle can be beneficial inconjunction with standard phlebotomy techniques during drug infusionand/or blood draw from a vein. Thus, while the embodiments and methodsare specifically described above in use on ocular tissue, it should beunderstood that the embodiments and methods have been presented by wayof example only, and not limitation.

While various embodiments have been described above, it should beunderstood that they have been presented by way of example only, and notlimitation. Where methods described above indicate certain eventsoccurring in certain order, the ordering of certain events may bemodified. Additionally, certain of the events may be performedconcurrently in a parallel process when possible, as well as performedsequentially as described above.

Although the systems and methods are shown and described herein asproviding for delivery of medicaments in the suprachoroidal space, inother embodiments, the systems and the methods described herein can beapplicable for delivery of any suitable therapeutic substance to anyportion of the eye, such as, the cornea, the retinal area or thevitreous. In other embodiments, any of the systems, methods and devicesdescribed herein can be used to deliver any suitable therapeuticsubstance to any desired target tissue (including non-ocular tissue).

In other embodiments, the cannulas, microneedles and/or methods can beused for delivery of medicaments into any suitable portion of the body,including dermal injections or the like.

Where schematics and/or embodiments described above indicate certaincomponents arranged in certain orientations or positions, thearrangement of components may be modified. Similarly, where methodsand/or events described above indicate certain events and/or proceduresoccurring in certain order, the ordering of certain events and/orprocedures may be modified. While the embodiments have been particularlyshown and described, it will be understood that various changes in formand details may be made.

Although various embodiments have been described as having particularfeatures and/or combinations of components, other embodiments arepossible having a combination of any features and/or components from anyof embodiments as discussed above.

1. An apparatus, comprising: a housing configured to receive at least aportion of a medicament container; a hub, the hub coupled to the housingand defining a passageway configured to receive a puncture membertherethrough, the hub having a distal end surface, the distal endsurface of the hub configured to contact a target surface of a targettissue when a substance is conveyed through the puncture member; and anactuation rod, the actuation rod configured to be coupled to themedicament container, the actuation rod and the puncture membercollectively configured such that (1) a distal end portion of theactuation rod moves within the medicament container and a length of thepuncture member extending distally from the distal end surface of thehub increases in response to a force on the actuation rod when a distalend portion of the puncture member is disposed within a first region ofthe target tissue, and (2) movement of the puncture member relative tothe distal end surface of the hub in response to the force on theactuation rod is limited when the distal end portion of the puncturemember is disposed within a second region of the target tissue, theforce having a magnitude less than a threshold value.
 2. The apparatusof claim 1, wherein the actuation rod and the puncture member arecollectively configured such that the length of the puncture memberextending distally from the distal end surface of the hub increases inresponse to the force on the actuation rod when the distal end portionof the puncture member is disposed within the first region of the targettissue and the distal end surface of the hub is in contact with thetarget surface of the target tissue.
 3. The apparatus of claim 1,wherein the threshold value is about 6 N.
 4. The apparatus of claim 1,wherein the force is between about 0.5 N and about 2 N.
 5. The apparatusof claim 1, wherein: the target tissue is an eye, the target surface isany one of a conjunctiva of the eye or a sclera of the eye, the firstregion includes at least one of a suprachoroidal space, a lower portionof the sclera, a choroid of the eye, a subretinal space of the eye, or aretina of the eye, the second region is an upper portion of the scleraof the eye the apparatus further comprising: the medicament containercontaining the substance, the substance being at least one of a VEGF, aVEGF inhibitor, a PDGFR inhibitor, or a combination thereof.
 6. Theapparatus of claim 1, wherein: the force is insufficient to convey thesubstance from the medicament container into the target tissue via thepuncture member when the distal end portion of the puncture member isdisposed within the first region of the target tissue.
 7. The apparatusof claim 1, wherein: the substance is conveyed through the puncturemember in response to the force on the actuation rod when the distal endportion of the puncture member is disposed within the second region ofthe target tissue.
 8. The apparatus of claim 1, wherein: the puncturemember is fixedly coupled to the hub such that the hub moves with thepuncture member when the puncture member is moved relative to the targetsurface.
 9. The apparatus of claim 1, wherein with the distal endsurface of the hub in contact with the target surface and the actuationrod coupled to the medicament container, the force on the actuation rodcauses the length of the puncture member extending distally from thedistal end surface of the hub to increase such that the distal endportion of the puncture member is moved from within the first region ofthe target tissue to the second region of the target tissue.
 10. Theapparatus of claim 1, wherein the force is sufficient to overcome abackpressure of the second region such that movement of the puncturemember relative to the distal end surface of the hub is reduced and thesubstance is conveyed into the target tissue when the distal end portionof the puncture member moves from the first region to the second region.11. The apparatus of claim 1, further comprising: a compressible memberoperably coupled to the medicament container, at least a portion of thepuncture member being disposed within a passageway defined by thecompressible member.
 12. The apparatus of claim 11, wherein thecompressible member is configured such that the length extendingdistally from the distal end surface of the hub cannot increase beyondabout 1200 μm in response to the force, the force being between about0.5 N and about 2 N.
 13. An apparatus, comprising: a housing configuredto receive at least a portion of a medicament container; a hub, the hubcoupled to the housing and defining a passageway configured to receive apuncture member therethrough, the hub having a distal end surface, thedistal end surface of the hub configured to contact a target surface ofa target tissue; a compressible member operably coupled to themedicament container; and an actuation rod, the actuation rod configuredto be coupled to the medicament container, the actuation rod, thecompressible member, and the puncture member collectively configuredsuch that (1) a distal end portion of the actuation rod moves within themedicament container and a length of the puncture member extendingdistally from the distal end surface of the hub increases in response toa force on the actuation rod when a distal end portion of the puncturemember is disposed within a first region of the target tissue, and (2)movement of the puncture member relative to the distal end surface ofthe hub in response to the force on the actuation rod is limited whenthe distal end portion of the puncture member is disposed within asecond region of the target tissue, the force having a magnitude lessthan a threshold value.
 14. The apparatus of claim 13, wherein theactuation rod, the compressible member, and the puncture member arecollectively configured such that the length of the puncture memberextending distally from the distal end surface of the hub increases inresponse to the force on the actuation rod when the distal end portionof the puncture member is disposed within the first region of the targettissue and the distal end surface of the hub is in contact with thetarget surface of the target tissue.
 15. The apparatus of claim 13,wherein at least one of the threshold value is about 6 N or the force isbetween about 0.5 N and about 2 N.
 16. The apparatus of claim 13,wherein: the target tissue is an eye, the target surface is any one of aconjunctiva of the eye or a sclera of the eye, the first region includesat least one of a suprachoroidal space, a lower portion of the sclera, achoroid of the eye, a subretinal space of the eye, or a retina of theeye, the second region is an upper portion of the sclera of the eye, theapparatus further comprising: the medicament container containing thesubstance, the substance being at least one of a VEGF, a VEGF inhibitor,a PDGFR inhibitor, or a combination thereof.
 17. The apparatus of claim13, wherein: the force is insufficient to convey the substance from themedicament container into the target tissue via the puncture member whenthe distal end portion of the puncture member is disposed within thefirst region of the target tissue.
 18. The apparatus of claim 13,wherein: the substance is conveyed through the puncture member inresponse to the force on the actuation rod when the distal end portionof the puncture member is disposed within the second region of thetarget tissue and the actuation rod is coupled to the medicamentcontainer.
 19. The apparatus of claim 13, wherein: the puncture memberis fixedly coupled to the hub such that the hub moves with the puncturemember when the puncture member is moved relative to the target surface.20. The apparatus of claim 13, wherein with the distal end surface ofthe hub in contact with the target surface and the actuation rod coupledto the medicament container, the force on the actuation rod causes thelength of the puncture member extending distally from the distal endsurface of the hub to increase such that the distal end portion of thepuncture member is moved from within the first region of the targettissue to the second region of the target tissue.
 21. The apparatus ofclaim 13, wherein the force is sufficient to overcome a backpressure ofthe second region such that movement of the puncture member relative tothe distal end surface of the hub is reduced and the substance isconveyed into the target tissue when the distal end portion of thepuncture member moves from the first region to the second region. 22.The apparatus of claim 13, wherein at least a portion of the puncturemember is disposed within a passageway defined by the compressiblemember.
 23. The apparatus of claim 13, wherein the compressible memberis configured such that the length extending distally from the distalend surface of the hub cannot increase beyond about 1200 μm in responseto the force, the force being between about 0.5 N and about 2 N.
 24. Amethod, comprising: inserting a distal end portion of a puncture memberof a medical injector into a target tissue to define a deliverypassageway within the target tissue and such that a distal end surfaceof a hub of the medical injector is in contact with a target surface ofthe target tissue; exerting a force on an actuation rod of the medicalinjector when the distal end surface of the hub is in contact with thetarget surface, the force having a magnitude of less than a thresholdvalue, the force produces movement of the actuation rod within amedicament container coupled to the medical injector and increases alength of the puncture member extending distally from the distal endsurface of the hub when the distal end portion of the puncture member isdisposed within a first region of the target tissue and the distal endsurface of the hub is in contact with the target surface of the targettissue; and conveying, in response to the exerting, a substance from themedicament container into the target tissue via the puncture member whenthe distal end portion of the puncture member is disposed within asecond region of the target tissue.
 25. The method of claim 24, whereinthe force increases the length of the puncture member extending distallyfrom the distal end surface of the hub when the distal end surface ofthe hub is in contact with the target surface such that the distal endportion of the puncture member is moved into the second region of thetarget tissue.
 26. The method of claim 24, wherein movement of thepuncture member relative to the distal end surface of the hub inresponse to the force is limited when the distal end portion of thepuncture member is disposed within the second region of the targettissue and the distal end surface of the hub is in contact with thetarget surface of the target tissue.
 27. The method of claim 24, whereinthe force is sufficient to overcome a backpressure of the second regionsuch that movement of the distal end portion of the puncture memberrelative to the hub is reduced and the substance is conveyed into thetarget tissue when the distal end portion of the puncture member movesfrom the first region to the second region.
 28. The method of claim 24,wherein: the threshold value is about 6 N, the target tissue is an eye,the target surface is any one of a conjunctiva of the eye or a sclera ofthe eye, the second region includes at least one of a suprachoroidalspace, a lower portion of the sclera, a choroid of the eye, a subretinalspace of the eye, or a retina of the eye, the substance being at leastone of a VEGF, a VEGF inhibitor, a PDGFR inhibitor, or a combinationthereof.
 29. The method of claim 24, further comprising: during theexerting the force, maintaining a force on the medical injector suchthat the hub forms a substantially fluid-tight seal with the targetsurface.
 30. The method of claim 24, wherein: the force is insufficientto convey the substance from the medicament container into the targettissue via the puncture member when the distal end portion of thepuncture member is disposed within the first region of the targettissue.